增龄性心房颤动心房重构的离子分子机制研究
|
摘要
目的：房颤的流行病学特征首先和年龄相关，伴随着人口老龄化等社会进步的表现，房颤的患病人数正迅速增加，房颤、老龄化是21世纪全世界必须面对的医疗与社会问题。因此，关注房颤、关注老年房颤就更具有重要的意义。基于房颤和增龄之间的密切关系，近年来国内外学者提出了增龄性房颤这一概念。本研究旨在探讨增龄性心房颤动心房重构的离子分子机制，以期为增龄性房颤的病因、发病机制和治疗等提供新的思路和理论依据。本研究目的是为探索与论证：1）是否心房肌细胞内钙离子平衡异常与左心房复极化障碍伴随增龄而显现，其是否为老年人易触发和易维持房颤的离子机制；2）是否存在心房肌细胞膜L-型钙通道蛋白和细胞内肌质网钙转运调控蛋白异常表达伴随增龄而显现，致使心肌细胞内钙稳态遭到破坏，其是否为增龄性房颤心房电重构的分子基质；3）是否心房肌细胞钙激活中性蛋白酶（calpain1、calpain2）、钙蛋白酶抑素（calpastatin）的表达变化与这种细胞内可能普遍存在的病理生理改变相关，包括在心房老化和房颤中左心房心肌细胞膜特征性的L-型钙通道表达改变、加速的纤维化和细胞凋亡，以期阐明增龄与房颤时心房肌电重构和结构重构以及心功能下降的分子生物学机制及其在增龄性房颤发生维持中的作用；4）伴随着心房老化或者在房颤这种疾病状态下，是否存在MMP-9与TIMP-1，BCL-2与BAX的表达改变与心房结构重构有关；5）是否可能存在的microRNA-1、microRNA-21、microRNA-29和microRNA-133的异常表达与伴随衰老和房颤疾病状态下加重的纤维化和细胞凋亡是否相关。方法：通过持续快速心房起搏建立持续性房颤犬模型，用全细胞膜片钳的方法记录4组犬（成年和老年窦性心律犬、成年和老年持续性房颤犬）的L-型钙电流（ICa-L）电流密度以及动作电位特征；用实时荧光定量聚合酶反应（Realtime PCR）和蛋白免疫印迹（Western blot）的方法针对四组犬：1）检测左心房心肌细胞膜L-型钙通道蛋白和肌浆网钙转运调控蛋白在mRNA和蛋白质表达水平变化；2）检测左心房肌细胞钙激活中性蛋白酶（calpain1、calpain2）、钙蛋白酶抑素（calpastatin）在mRNA和蛋白质表达水平变化；3）检测左心房肌细胞MMP-9与TIMP-1，BCL-2与BAX在mRNA和蛋白质表达水平变化；4）检测左心房肌细胞microRNA-1、microRNA-21、microRNA-29和microRNA-133的表达变化；5）应用光镜、电镜及TUNEL法检测各组犬左心房心肌组织细胞的超微结构变化、心肌纤维化程度以及细胞凋亡指数等结构重构；6）检测目标基因及蛋白的表达变化与心房电重构及结构重构之间是否存在相关性。结果：1.电生理变化：1）窦性心律时体表心电图数据显示，与成年犬比较，老年犬的心电图P波持续时间显著地延长，P波离散度显著地增大（P＜0.05）；2）在窦性心律时成年犬和老年犬左心房组织细胞动作电位的特征性变化趋势：与成年犬比较，老年犬的心肌细胞膜动作电位平台期（2相）电压显著降低，动作电位持续时间（APD90）显著延长，L-型钙电流密度出现了明显地减低（均P＜0.05）；3）与窦性心律时比较，两组犬在发生房颤时均出现了显著的去极化趋势，均出现动作电位持续时间（APD90）缩短，动作电位振幅显著地增大，平台期电位电势显著地减少，L-型钙电流密度出现了显著地减低（均P＜0.05）。2.分子生物学变化：1）在mRNA和蛋白质表达水平，老年犬左心房肌LVDCCa1c显著地降低，而Ca2+-ATPase显著地升高（均P＜0.05），RYR2，IP3R1和PLN普遍地显示出上调的趋势，但无统计学差异（P＞0.05）；与窦性心律犬比较，房颤犬除受磷蛋白（PLN）之外，LVDCCa1c和肌浆网钙转运调控蛋白均显著地下调，尤其是老年房颤犬这种下调趋势更加明显（（均P＜0.05））；2）与成年犬比较，老年犬左心房肌细胞calpain1，calpain2和calpastatin在mRNA和蛋白质表达水平均普遍地显示出上调的趋势，但是未显示出统计学差异（P＞0.05）。此外，在相同年龄的窦性心律犬和慢性房颤犬之间的比较中显示，房颤犬左心房肌细胞calpain1在mRNA和蛋白质表达水平均显著地增高（均P＜0.05），尤其是老年房颤犬增高最为明显；然而，calpain2和calpastatin在mRNA和蛋白质表达水平均未显示出统计学差异（均P＞0.05），老年房颤犬的LVDCCa1c与calpain1在蛋白质表达水平呈现负相关（r=-0.583，P=0.019）；3）与成年犬比较，老年犬左心房肌细胞MMP-9和BAX在mRNA和蛋白质表达水平表达均显著地增高（均P＜0.05），而TIMP-1和BCL-2表达均显著地下降（均P＜0.05）；与窦性心律犬比较，房颤犬左心房肌细胞MMP-9和BAX在mRNA和蛋白质表达水平均显现出有意义的上调趋势（均P＜0.05），尤其是老年房颤犬最为明显，TIMP-1和BCL-2在mRNA和蛋白质表达水平均显现出有意义的下调趋势（均P＜0.05），尤其是老年房颤犬最为明显；4）与成年犬组相比较，在窦性心律时老年犬左心房肌细胞miR-21，29的表达水平显现出显著的上调趋势（均P＜0.05）；然而，miR-1，133的表达水平呈现出显著的下调趋势（均P＜0.05）；与窦性心律老年犬组相比较，在持续性房颤老年组犬左心房心肌组织的miR-1，21，29的表达水平显现出显著的上调趋势（均P＜0.05）；miR-133的表达水平显现出显著的下调趋势（P＜0.05）。3.组织病理学变化：伴随老龄与房颤，犬心肌纤维化程度、细胞超微结构及凋亡指数均显现出有统计学意义的改变（均P＜0.05）。结论：1）这种伴随增龄与房颤而显现的左房电生理和钙转运调控蛋白特异性改变（适应与不良适应反应）可能是增龄性房颤心房电重构的分子基质之一。2）这种伴随增龄与房颤而显现的钙激活中性蛋白酶特异性生物活性改变可能是增龄性房颤心房电重构与结构重构的分子基质之一。3）这种伴随增龄与房颤而显现的MMP-9与TIMP-1，BCL-2与BAX特异性的生物活性改变可能是增龄性房颤心房纤维化重构的分子基质之一。4）这种伴随增龄与房颤而显现的microRNA-1、microRNA-21、microRNA-29和microRNA-133的异常表达与心房结构重构进程中特征性的加重的纤维化和细胞凋亡相关，其对将来可能的临床诊断、预后评估及基因治疗与干预提供了有意义思路和措施。
Objective: This study was to investigate whether or not the dysfunction of atrialrepolarization and abnormality of the intracellular Ca2+handling protein was augmentedwith aging; to investigate the correlation between the change in the expression of atrialcalpains and electrical, molecular, and structural remodeling during aging and AF; toinvestigate whether abnormal expressions of matrix metalloproteinase (MMP)-9/tissueinhibitors of MMPs (TIMP)-1and BCL-2/BAX are correlated with the characteristicaccelerated fibrosis and apoptosis during aging and AF; to investigate whether or not theaberrant expression of microRNA-1, microRNA-21, microRNA-29and microRNA-133show a correlation with structural remodeling during aging and AF, and demonstrate thatthese miRNAs, acting singly or in combination, may be responsible for modulating thetransition from adaption to pathological atrial remodelling. Methods: Four groups ofdogs were studied; younger adult and aged dogs in sinus rhythm (SR) and atrialfibrillation (AF) induced by rapid atrial pacing. We used whole cell patch clamprecording techniques to measure L-type Ca2+current (ICa-L) in cells dispersed from theleft atria. The mRNA and protein expressions of the target proteins in the left atrium weremeasured by quantitative RT-PCR and Western blot analysis. The expressions of thetarget microRNAs were measured by Quantitative Real-Time Polymerase Chain Reaction(qRT-PCR). Pathohistological and ultrastructural changes were tested by light andelectron microscopy. Apoptosis indices of myocytes were detected by TUNEL. Results:In SR groups, atrial cells of the old dogs had longer action potential (AP) duration to90%repolarization (APD90), lower AP plateau potential, and peak ICa-Lcurrent densities(all P＜0.05). In both ages, AF led to a higher maximum diastolic potential, a increase ofAP amplitude, decreases of APD90, AP plateau potential and peak ICa-Ldensities (all P＜ 0.05). Compared to the adult group, the mRNA and protein expressions of LVDCCa1cwere decreased in the aged group, whereas the expressions of calcium adenosinetriphosphatase were increased; the mRNA and protein expressions of MMP-9and BAXand those of TIMP-1and BCL-2exhibited a significant increase and a down-regulationpattern, respectively, in the aged groups compared with the adult groups; compared to theadult group, the expressions of miR-21,29was significantly increased, whereas theexpressions of miR-1,133showed obviously down-regulation tendence in the aged group(all P＜0.05). Compared to SR group, expressions of LVDCCa1c and Ca2+handlingprotein except for phospholamban were significantly decreased in both age groups withAF; the mRNA and protein expressions of calpain1were increased in both the adult andold groups with AF; compared with the control groups, the adult and old groups with AFexhibited significantly increased mRNA and protein expressions of MMP-9and BAXand down-regulated expressions of TIMP-1and BCL-2; compared to the aged group, theexpressions of miR-1,21,29was significantly increased in the old group in AF, incontrast, the expressions of miR-133showed obviously down-regulation tendence (all P＜0.05). Samples of atrial tissue showed abnormal pathohistological and ultrastructuralchanges like accelerated fibrosis and apoptosis with aging and in AF (all P＜0.05).Conclusions: These aging-induced electrophysiological and molecular changes showedthat general pathophysiological adaptations might provide a substrate conducive to AF.Age-related alterations in atrial tissues can be attributed to increased expressions ofcalpain1. MMP-9/TIMP-1and BCL-2/BAX hold potential for use as substratesconducive to AF, and their abnormal expressions play a major role in atrial structuralremodelling. These multiple aberrantly expressed miRNAs may be responsible formodulating the transition from adaption to pathological atrial remodelling with agingand/or in AF.
Objective: This study was to investigate whether or not the dysfunction of atrialrepolarization and abnormality of the intracellular Ca2+handling protein was augmentedwith aging; to investigate the correlation between the change in the expression of atrialcalpains and electrical, molecular, and structural remodeling during aging and AF; toinvestigate whether abnormal expressions of matrix metalloproteinase (MMP)-9/tissueinhibitors of MMPs (TIMP)-1and BCL-2/BAX are correlated with the characteristicaccelerated fibrosis and apoptosis during aging and AF; to investigate whether or not theaberrant expression of microRNA-1, microRNA-21, microRNA-29and microRNA-133show a correlation with structural remodeling during aging and AF, and demonstrate thatthese miRNAs, acting singly or in combination, may be responsible for modulating thetransition from adaption to pathological atrial remodelling. Methods: Four groups ofdogs were studied; younger adult and aged dogs in sinus rhythm (SR) and atrialfibrillation (AF) induced by rapid atrial pacing. We used whole cell patch clamprecording techniques to measure L-type Ca2+current (ICa-L) in cells dispersed from theleft atria. The mRNA and protein expressions of the target proteins in the left atrium weremeasured by quantitative RT-PCR and Western blot analysis. The expressions of thetarget microRNAs were measured by Quantitative Real-Time Polymerase Chain Reaction(qRT-PCR). Pathohistological and ultrastructural changes were tested by light andelectron microscopy. Apoptosis indices of myocytes were detected by TUNEL. Results:In SR groups, atrial cells of the old dogs had longer action potential (AP) duration to90%repolarization (APD90), lower AP plateau potential, and peak ICa-Lcurrent densities(all P＜0.05). In both ages, AF led to a higher maximum diastolic potential, a increase ofAP amplitude, decreases of APD90, AP plateau potential and peak ICa-Ldensities (all P＜ 0.05). Compared to the adult group, the mRNA and protein expressions of LVDCCa1cwere decreased in the aged group, whereas the expressions of calcium adenosinetriphosphatase were increased; the mRNA and protein expressions of MMP-9and BAXand those of TIMP-1and BCL-2exhibited a significant increase and a down-regulationpattern, respectively, in the aged groups compared with the adult groups; compared to theadult group, the expressions of miR-21,29was significantly increased, whereas theexpressions of miR-1,133showed obviously down-regulation tendence in the aged group(all P＜0.05). Compared to SR group, expressions of LVDCCa1c and Ca2+handlingprotein except for phospholamban were significantly decreased in both age groups withAF; the mRNA and protein expressions of calpain1were increased in both the adult andold groups with AF; compared with the control groups, the adult and old groups with AFexhibited significantly increased mRNA and protein expressions of MMP-9and BAXand down-regulated expressions of TIMP-1and BCL-2; compared to the aged group, theexpressions of miR-1,21,29was significantly increased in the old group in AF, incontrast, the expressions of miR-133showed obviously down-regulation tendence (all P＜0.05). Samples of atrial tissue showed abnormal pathohistological and ultrastructuralchanges like accelerated fibrosis and apoptosis with aging and in AF (all P＜0.05).Conclusions: These aging-induced electrophysiological and molecular changes showedthat general pathophysiological adaptations might provide a substrate conducive to AF.Age-related alterations in atrial tissues can be attributed to increased expressions ofcalpain1. MMP-9/TIMP-1and BCL-2/BAX hold potential for use as substratesconducive to AF, and their abnormal expressions play a major role in atrial structuralremodelling. These multiple aberrantly expressed miRNAs may be responsible formodulating the transition from adaption to pathological atrial remodelling with agingand/or in AF.
引文
[1] Furberg CD, Psaty BM, Manolio TA, et al. Prevalence of atrial fibrillation in elderlysubjects[J]. Am J Cardiol.1994,74:236-41.
[2] ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation[J].Eur Heart J.2001,22:1852-1932.
[3] Tsang TS, Miyasaka Y, Barnes ME, et al. Epidemiological profile of atrialfibrillation:a contemporary perspective[J]. Prog Cardiovasc Dis.2005,48:1-8.
[4] Mazzini MJ, Monahan KM. Pharmacotherapy for atrial arrhythmias:present andfuture[J]. Heart Rhythm.2008,5:S26-31.
[5] Nattel S. New ideas about atrial fibrillation50years on[J]. Nature.2002,415:219-26.
[6] Chen LY, Shen W-K. Epidemiology of atrial fibrillation:A current perspective[J].Heart Rhythm.2007,4:S1-S6.
[7] Allessie MA, Boyden PA, Camm AJ, et al. Pathophysiology and prevention of atrialfibrillation[J]. Circulation.2001;103:769-777.
[8] Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime Risk for Development of AtrialFibrillation The Framingham Heart Study[J]. Circulation,2004;110(3):1042-1046.
[9]中华医学会心血管病分会.中国部分地区心房颤动住院病例回顾性调查[J].中华心血管病杂志.2003,31(4):913-916.
[10] Yue L, Feng J, Gaspo R, et al. Ionic remodeling underlying action potential changesin a canine model of atrial fibrillation[J]. Circ Res.1997,81:512-525.
[11] Brundel B. J. J. M, Van Gelder I. C, Henning R. H, et al. Ion channel remodeling isrelated to intra-operative atrial refractory periods in patients with paroxysmal andpersistent atrial fibrillation[J]. Circulation.2001,103:684-690.
[12] Cha TJ, Ehrlich JR, Zhang L, et al. Dissociation between ionic remodeling andability to sustain atrial fibrillation during recovery from experimental congestiveheart failure[J]. Circulation.2004,109:412-418.
[13] Ausma J, Wijffels M, Thone F, et al. Structural changes of atrial myocardium due tosustained atrial fibrillation in the goat[J]. Circulation.1997,96:3157-3163.
[14] Thijssen V. L. J. L, Ausma J, Liu G. S, et al. Structural changes of atrial myocardiumduring chronic atrial fibrillation[J]. Cardiovasc Pathol.2000,9:17-28.
[15] Courtemanche M, Ramirez R. F, Nattel S. Ionic mechanisms underlying humanatrial action potential properties:insights from a mathematical model[J]. Am JPhysiol.1998,275:H301-H321.
[16] Nattel S. Atrial electrophysiological remodeling caused by rapid atrial activation:underlying mechanisms and clinical relevance to atrial fibrillation[J]. Cardiovasc Res.1999,42:298-308.
[17] Yue L, Melnyk P, Gaspo R, et al. Molecular mechanisms underlying ionicremodeling in a dog model of atrial fibrillation[J]. Circ Res.1999,84:776-784.
[18] Van Wagoner D. R, Pond A. L, McCarthy P. M, et al. Outward K+current densitiesand Kv1.5expression are reduced in chronic human atrial fibrillation[J]. Circ Res.1997,80:1-10.
[19] Van Wagoner D. R, Pond A. L, Lamorgese M, et al. Atrial L-type Ca2+currents andhuman atrial fibrillation[J]. Circ Res.1999,85:428-436.
[20] Gaspo R, Bosch R. F, Bou-Abboud E, et al. Tachycardia-induced changes in Na+current in a chronic dog model of atrial fibrillation[J]. Circ Res.1997,81:1045-1052.
[21] Brundel B. J. J. M, Van Gelder I. C, Henning R. H, et al. Alterations in potassiumchannel gene expression in atria of patients with persistent and paroxysmal atrialfibrillation[J]. J Am Coll Cardiol.2001,37:926-932.
[22] Dobrev D, Graf E, Wettwer E, et al. Molecular basis of downregulation ofG-protein-coupled inward rectifying K+current(IK, ACh)in chronic human atrialfibrilation[J]. Circulation.2001,104:2551-2557.
[23] Coutu P, Chartier D, Nattel S. Comparison of Ca2+handling properties of caninepulmonary vein and left atrial cardiomyocytes[J]. Am J Physiol Heart Circ Physiol.2006,291:H2290-H2300.
[24] El-Armouche A, Boknik P, Eschenhagen T, et al. Molecular determinants of alteredCa2+handling in human chronic atrial fibrillation[J]. Circulation.2006,114:670-680.
[25] Kubalova Z, Gyorke I, Terentyeva R, et al. Modulation of cytosolic and intra-sarcoplasmic reticulum calcium waves by calsequestrin in rat cardiac myocytes[J]. JPhysiol.2004,561:515-524.
[26] Terentyev D, Nori A, Santoro M, et al. Abnormal interactions of calsequestrin withthe ryanodine receptor calcium release channel complex linked to exercise-inducedsudden cardiac death[J]. Circ Res.2006,98:1151-1158.
[27] Wijffels M. C, Kirchhof C. J, Dorland R, et al. Atrial fibrillation begets atrialfibrillation:A study in awake chronically instrumented goats[J]. Circulation.1995,92:1954-1968.
[28] Ausma J, Wijffels M, Thone F, et al. Structural Changes of atrial myocardium due tosustained atrial fibrillation in the goat[J]. Circulation.1997,96:3157-3163.
[29] Daoud EG, Bogun F, Goyal R, et al. Effect of atrial fibrillation on atrialrefractoriness in humans[J]. Circulation.1996,94:1600-1606.
[30] Frustaci A, Chimenti C, Bellocci F, et al. Histological substrate of atrial biopsies inpatients with lone atrial fibrillation[J]. Circulation.1997,96:1180-1184.
[31] Goette A, Honeycutt C, Langberg JJ. Electrical remodeling in atrial fibrillation:Timecourse and mechanisms[J]. Circulation.1996,94:2968-2974.
[32] Ausma J, Dispersyn GD, Duimel H, et al. Changes in ultrastructural calciumdistribution in goat atria during atrial fibrillation[J]. J Mol Cell Cardiol.2000,32:355-364.
[33] Schotten U, Ausma J, Stellbrink C, et al. Cellular mechanisms of depressed atrialcontractility in patients with chronic atrial fibrillation[J]. Circulation.2001,103:691-698.
[34] Jayachandran JV, Zipes DP, Weksler J, et al. Role of the Na+/H+exchanger inshort-term atrial electrophysiological remodeling[J]. Circulation.2000,101:1861-1866.
[35] Gao WD, Atar D, Liu Y, et al. Role of troponin I proteolysis in the pathogenesis ofstunned myocardium[J]. Circ Res.1997,80:393-399.
[36] Gurevitch J, Frolkis I, Yuhas Y, et al. Anti-tumor necrosis factor-alpha improvesmyocardial recovery after ischemia and reperfusion[J]. J Am Coll Cardiol.1997,30:1554-1561.
[37] Ke L, Qi XY, Dijkhuis AJ, et al. Calpain mediates cardiac troponin degradation andcontractile dysfunction in atrial fibrillation[J]. J Mol Cell Cardiol.2008,45:685-693.
[38] Brundel BJ, Ausma J, van Gelder IC, et al. Activation of proteolysis by calpains andstructural changes in human paroxysmal and persistent atrial fibrillation[J].Cardiovasc Res.2002,54(2):380-389.
[39] Hyun DH, Hernandez JO, Mattson MP, et al. The plasma membrane redox system inaging[J]. Ageing Res Rev.2006,5:209-220.
[40] Blasco MA. Telomeres and human disease:ageing, cancer and beyond[J]. Nat RevGenet.2005,6:611-622.
[41] Go AS. The epidemiology of atrial fibrillation in elderly persons:the tip of theiceberg[J]. Am J Geriatr Cardiol.2005,14:56-61.
[42] Anyukhovsky EP, Sosunov EA, Chandra P, et al. Age-associated changes inelectrophysiologic remodeling:a potential contributor to initiation of atrialfibrillation[J]. Cardiovasc Res.2005,66:353-363.
[43] Anyukhovsky EP, Sosunov EA, Plotnikov A, et al. Cellular electrophysiologicproperties of old canine atria provide a substrate for arrhythmogenesis[J].Cardiovasc Res.2002,54:462-469.
[44] Weber KT, Pick R, Jalil JE, et al. Patterns of myocardial fibrosis[J]. J Mol CellCardiol.1989,21(Suppl5):121-131.
[45] Allessie M, Schotten U, Verheule S, et al. Gene therapy for repair of cardiacfibrosis:A long way to Tipperary[J]. Circulation.2005,111:391-393.
[46] Spach MS, Heidlage JF, Barr RC, et al. Cell size and communication:role instructural and electrical development and remodeling of the heart[J]. Heart Rhythm.2004,1:500-515.
[47] Spach MS, Dolber PC. Relating extracellular potentials and their derivatives toanisotropic propagation at a microscopic level in human cardiac muscle:Evidencefor electrical uncoupling of side-to-side fiber connections with increasing age[J].Circ Res.1986,58:356-371.
[48] de Bakker JM, van Rijen HM. Continuous and discontinuous propagation in heartmuscle[J]. J Cardiovasc Electrophysiol.2006,17:567-573.
[49] Narayan SM, Bode F, Karasik PL, et al. Alternans of atrial action potentialsduring atrial flutter as a precursor to atrial fibrillation[J]. Circulation.2002,106:1968-1973.
[50] Spach MS, Heidlage JF, Dolber PC, et al. Mechanism of origin of conductiondisturbances in aging human atrial bundles:experimental and model study[J]. HeartRhythm.2007,4:175-185.
[51] Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at amicroscopic level:Electrical description of myocardial architecture and itsapplication to conduction[J]. Circ Res.1995,76:366-380.
[52] Nygren A, Fiset C, Firek L, et al. Mathematical model of an adult human atrialcell:the role of K+currents in repolarization[J]. Circ Res.1998,82:63-81.
[53] Chen PS, Wolf PD, Dixon EG, et al. Mechanism of ventricular vulnerability tosingle premature stimuli in open-chest dogs[J]. Circ Res.1988,62:1191-1209.
[54] Dobrev D, Ravens U. Remodeling of cardiomyocyte ion channels in human atrialfibrillation[J]. Basic Res Cardiol.2003,98:137-148.
[55] Dhamoon AS, Jalife J. The inward rectifier current(IK1)controls cardiac excitabilityand is involved in arrhythmogenesis[J]. Heart Rhythm.2005,2:316-324.
[56] Jalife J. Rotors and spiral waves in atrial fibrillation[J]. J Cardiovasc Electrophysiol.2003,14:776-780.
[57] Miragoli M, Gaudesius G, Rohr S. Electrotonic modulation of cardiac impulseconduction by myofibroblasts[J]. Circ Res.2006,98:801-810.
[58] Camelliti P, Green CR, LeGrice I, et al. Fibroblast network in rabbit sinoatrialnode:structural and functional identification of homogeneous and heterogeneouscell coupling[J]. Circ Res.2004,94:828-835.
[59] Kamkin A, Kiseleva I, Isenberg G, et al. Cardiac fibroblasts and themechano-electric feedback mechanism in healthy and aged hearts[J]. Prog BiophysMol Biol.2003,82:111-120.
[60] Bartel DP. MicroRNAs, genomics, biogenesis, mechanism and function[J]. Cell.2008,116:281-297.
[61] van Rooij E, Sutherland LB, Qi X, et al. Control of stress-dependent cardiac growthand gene expression by a microRNA[J]. Science.2007,316:575-579.
[62] Zhao Y, Samal E, Srivastava D. Serum response factor regulates a muscle-specificmicroRNA that targets Hand2during cardiogenesis[J]. Nature.2005,436(7048):214-220.
[63] Yang B, Lin H, Xiao J, et al. The muscle-specific microRNA miR-1regulatescardiac arrhythmogenic potential by targeting GJA1and KCNJ2[J]. Nat Med.2007,13(4):486-491.
[64] Zhao Y, Ransom JF, Li A, et al. Dysregulation of cardiogenesis, cardiac conductionand cell cycle in mice lacking miRNA-1[J]. Cell.2007,129(2):303-317.
[65] van Rooij E, Sutherland LB, Liu N, et al. A signature pattern of stress-responsivemicroRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl AcadSci USA.2006;103(48):18255-18260.
[66] Xiao J, Luo X, Lin H, et al. MicroRNA miR-133represses HERG K+channelexpression contributing to QT prolongation in diabetic hearts[J]. J Biol Chem.2007,282(17):12363-12367.
[67] Thum T, Galuppo P, Wolf C, et al. MicroRNAs in the human heart-a clue to fetalgene reprogramming in heart failure[J]. Circulation.2007,116(3):258-267.
[68] Wang GK, Zhu JQ, Zhang JT, et al. Circulating microRNA:a novel potentialbiomarker for early diagnosis of acute myocardial infarction in humans[J]. EurHeart J.2010,31(6):659-666.
[69] Tijsen AJ, Creemers EE, Moerland PD, et al. MiR423-5p as a circulating biomarkerfor heart failure[J]. Circ Res.2010,106(6):1035-1039.
[70] Matkovich SJ, van Booven DJ, Youker KA, et al. Reciprocal regulation ofmyocardial microRNAs and messenger RNA in human cardiomyopathy andreversal of the microRNA signature by biomechanical support[J]. Circulation.2009,119(9):1263-1271.
[71] Schipper ME, van Kuik J, de Jonge N, et al. Changes in regulatory microRNAexpression in myocardium of heart failure patients on left ventricular assist devicesupport[J]. J Heart Lung Transplant.2008,27(12):1282-1285.
[72] Krutzfeldt J, Rajewsky N, Braich R, et al. Silencing of microRNAs in vivo with‘antagomirs’ Nature[J].2005,438(7068):685-689.
[73] van Rooij E, Sutherland LB, Thatcher JE, et al. Dysregulation of microRNAs aftermyocardial infarction reveals a role of miR-29in cardiac fibrosis[J]. Proc Natl AcadSci USA.2008,105:13027-13032.
[74] Care A, Catalucci D, Felicetti F, et al. MicroRNA-133controls cardiachypertrophy[J]. Nat Med.2007,13(5):613-618.
[75] Thum T, Gross C, Fiedler J, et al. MicroRNA-21contributes to myocardial diseaseby stimulating MAP kinase signalling in fibroblasts[J]. Nature.2008,456(7224):980-984.
[76] Lin Z, Murtaza I, Wang K, et al. MiR-23a functions downstream of NFATc3toregulate cardiac hypertrophy[J]. Proc Natl Acad Sci USA.2009,106(29):12103-12108.
[77] Esau C, Davis S, Murray SF, et al. MiR-122regulation of lipid metabolism revealedby in vivo antisense targeting[J]. Cell Metab.2006,3(2):87-98.
[78] Elmen J, Lindow M, Schutz S, et al. LNA-mediated microRNA silencing innon-human primates[J]. Nature.2008,452(7189):896-899.
[79] Suckau L, Fechner H, Chemaly E, et al. Long-term cardiac-targeted RNAinterference for the treatment of heart failure restores cardiac function and reducespathological hypertrophy[J]. Circulation.2009,119(9):1241-1252.
[80] Wen Dun1, Takuya Yagi1, Michael R, et al. Calcium and potassium currents in cellsfrom adult and aged canine right atria[J]. Cardiovascular Research.2003,58:526-534.
[81] Josephson IR, Guia A, Stern MD, et al. Alterations in properties of L-type Ca2+channels in aging heart[J]. J Mol Cell Cardiol.2002,34:297-308.
[82] Sosunov EA, Anyukhovsky EP, Rosen MR. The adrenergic-cholinergic interactionthat modulates repolarization in the atrium is altered with aging[J]. J CardiovascElectrophysiol.2002,13:374-379.
[83] Chou CC, Nihei M, Zhou S, et al. Intracellular calcium dynamics and anisotropicreentry in isolated canine pulmonary veins and left atrium[J]. Circulation.2005,111:2889-2897.
[84] Nattel S, Maguy A, Le Bouter S, et al. Arrhythmogenic ion-channel remodelling inthe heart:heart failure, myocardial infarction, and atrial fibrillation[J]. Physiol Rev.2007,87:425-456.
[85] Van Gelder IC, Brundel BJ, Henning RH, et al. Alterations in gene expression ofproteins involved in the calcium handling in patients with atrial fibrillation[J]. JCardiovasc Electrophysiol.1999,10:552-60.
[86] Brundel BJ, Van Gelder IC, Henning RH, et al. Gene expression of proteinsinfluencing the calcium homeostasis in patients with persistent and paroxysmalatrial fibrillation[J]. Cardiovasc Res.1999,42:443-454.
[87] Vest JA, Wehrens XH, Reiken SR, et al. Defective cardiac ryanodine receptorregulation during atrial fibrillation[J]. Circulation.2005,111:2025-2032.
[88] S. Neef, N. Dybkova, S. Sossalla, K. R, et al. CaMKII-Dependent Diastolic SR Ca2+Leak and Elevated Diastolic Ca2+Levels in Right Atrial Myocardium of PatientsWith Atrial Fibrillation[J]. Circ Res.2010,106:1134-1144.
[89] Bers Dm. Excitation-Contraction Coupling and Cardiac Contractile Force.[J]ZDordrecht, Netherlands, Kluwer Academic Publishers.2001.
[90] ZBers DM, Perez-Reyes E. Ca channels in cardiac myocytes:Structure and functionin ZZCa influx and intracellular ZCa release[J]. Cardiovasc Res.1999,42:339-360.
[91] Bean BP. Classes of calcium channels in vertebrate cells[J]. Annu Rev Physiol.1989,51:367-384.
[92] Bean BP. Two kinds of calcium channels in canine atrial cels. ZDifferences inkinetics, selectivity, and pharmacology[J]. JZ Gen Physio.1985, l86:1-30.
[93] Hirano Y, Fozzard HA, January ZCT. Characteristics of L-and T-type Ca2+currentsin canine cardiac Purkinje cells[J]. Am J Physiol Heart Circ Physiol.1989,256:H1478-H1492.
[94] Hagiwara N, Irisawa H, Kameyama M. Contribution of two types of calciumcurrents to the pacemaker potentials of rabbit sino-atrial node cells[J]. J Physiol.1988,359:233-253.
[95] Mitra R, Morad M. Two types of calcium channels in guinea-pig ventricularmyocytes[J]. Proc Natl Acad Sci U S A.1986,83:5340-5344.
[96] Nuss HB, Houser SR. T-type Ca2+current is expressed in hypertrophied adult felineleft ventricular myocytes[J]. Circ Res.1993,73:777-782.
[97] Yuan W, Bets DM. Ca-dependent facilitation of cardiac Ca current is due toCa-calmodulin-dependent protein kinase[J]. Am J Physiol Heart Circ Physiol.1994,267:H982-H993.
[98] Yuan W, Ginsburg KS, Bers DM. Comparison of sarcolemmal calcium channelcurrent in rabbit and rat ventricular myocytes[J]. J Physiol.1996,493:733-746.
[99] Wetzel GT, Chen F, Klitzner TS. Ca2+channel kinetics in acutely isolated fetal,neonatal, and adult rabbit cardiac myocytes[J]. Circ Res.1993,72:1065-1074.
[100]GaughanJP, Hefner CA, Houser SR. Electrophysiological properties of neonatal ratventricular myocytes with α1-adrenergic-induced hypertrophy[J]. AmJ PhysiolHeart Circ Physio.1998,1275:H577-H590.
[101]Cribbs LL, Martin BL, Schroder EA, et al Identification of the T-type calciumchannel(Cav3.1d)in developing mouse heart[J]. Circ Res.2001,88:403-407.
[102]Martfnez ML, Heredia MP, Delgado C. Expression of T-type Ca2+channels inventricular cells from hypertrophied rat hearts[J]. J Mol Cell Cardiol.1999,31:1617-1625.
[103]Jeong SW, Wurster RD. Calcium channel currents in acutely dissociatedintracardiac neurons from adult rats[J]. J Neurophysiol.1997,77:1769-1778.
[104]Lipsius SL, Hiiser J, Blatter LA. Intracellular Ca release sparks atrial pacemakeractivity[J]. News Physiol Sci.2001,16:101-106.
[105]Ruth P, R6hrkasten A, Biel M, et al. Primary structure of the3subunit of theDHP-sensitive calcium channel from skeletal muscle[J]. Science.1989,245:1115-1118.
[106]Jay SD, Ellis SB, McCue A. F, et al. Primary structure of the7subunit of theDHP-sensitive calcium channel from skeletal muscle[J]. Science1990;248:490-492.
[107]Mikami A, Imoto K, Tanabe T, et al. Primary structure and functional expression ofthe cardiac dihydropyridine-sensifive calcium channel[J]. Nature.1989,340:230-233.
[108]Takimoto K, Li D, Nerbonne JM, Levitan ES. Distribution, splicing andglucocorticoid-induced expression of cardiac voltage-gated Ca2+channelmRNAs[J]. J Mol Cell Cardio.1997,129:3035-3042.
[109]Wyatt CN, Campbell V, Brodbeck J, et al. Voltage-dependent binding and calciumchannel current inhibition by an anti-α1D subunit antibody in rat dorsal rootganglion neurones and guinea-pig myocytes[J]. J Physiol.1997,502:307-319.
[110]Jay SD, Sharp AH, Kahl SD, et al. Structural characterization of thedihydropyridine-sensitive calcium channel a1c-subunit and the associated8peptides[J]. J Biol Chem.1991,266:3287-3293.
[111]Wei XY, Pan S, Lang WH, et al. Molecular determinants of cardiac Ca2+channelpharmacology--Subunit requirement for the high affinity and allosteric regulation ofdihydropyridine binding[J]. J Biol Chem.1995,270:27106-27111.
[112]Bangalore R, Mehrke G, Gingrich K, et al. Influence of L-type Ca channela1c-subunit on ionic and gating current in transiently transfected HEK293cells[J].Am J Physiol Heart Circ Physiol.1996,270:H152i-H1528.
[113]Perez-Reyes E, Castellano A, Kim HS, et al. Cloning and expression of acardiac/brain ubunit of the L-type calcium channel[J]. J Biol Chem.1992,267:1792-1797.
[114]Neely A, Wei X, Olcese R, et al. Potentiation by the13subunit of the ratio of theionic current to the charge movement in the cardiac calcium channel[J]. Science.1993,262:575-578.
[115]Mitterdorfer J, Froschmayr M, Grabner M, et al. Calcium channels:The β-subunitincreases the affinity of dihydropyridine and Ca2+binding sites of the α1-subunit[J].FEBS Lett.1994,352:141-145.
[116]Gao TY, Chien AJ, Hosey MM. Complexes of the α1c and β subunits generate thenecessary signal for membrane targeting of class C L-type calcium channels[J]. JBiol Chem.1999,274:2137-2144.
[117]de Waard M, Pragnell M, Campbell KP. Ca2+channel regulation by a conservedsubunit domain[J]. Neuron.1994,13:495-503.
[118]Pragnell M, de Waard M, Mori Y, et al. Calcium channel a1c-subunit binds to aconserved motif in the I-II cytoplasmic linker of the α1-subunit[J]. Nature.1994,368:67-70.
[119]Perez-Reyes E, Cribbs LL, et al. Molecular characterization of a neuronallow-voltage-activated T-type calcium channel[J]. Nature.1998,391:896-900.
[120]Cribbs LL, Lee JH, Yang J, et al. Cloning and characterization of cdH from humanheart, a member of the T-type Ca2+channel gene family[J]. Circ Res.1998,83:103-109.
[121]Lee JH, Daud AN, Cribbs LL, et al. Cloning and expression of a novel member ofthe low voltage-activated T-type calcium channel family[J]. J Neurosci.1999,19:1912-1921.
[122]McCIeskey EW, Ahners W. The Ca channel in skeletal muscle is a large pore[J].Proc Nad Acad Sci U S A.1985,82:7149-7153.
[123]Ellinor PT, Yang J, Sather WA, et al. Ca2+channel selectivity at a single locus forhigh-affinity Ca2+interactions[J]. Neuron.1995,15:1121-1132.
[124]Chen XH, Bezprozvanny I, Tsien RW. Molecular basis of proton block of L-typeCa2+channels[J]. J Gen Physiol.1996,108:363-374.
[125]Chen XH, Tsien RW. Aspartate substitutions establish the concerted action ofP-region glutamates in repeats I and III in forming the pro-tonation site of L-typeCa2+channels[J]. J Biol Chem.1997,272:30002-30008.
[126]Lee KS, Marban E, Tsien RW. Inactivation of calcium channels in mammalian heartcells:Joint dependence on membrane potential and intracellular calcium[J]. JPhysiol.1985,364:395-411.
[127]Kass RS, Sanguinetti MC. Inactivation of calcium channel current in the calfcardiac Purkinje fiber:Evidence for voltage-and calcium-mediated mechanisms[J]. JGen Physiol.1984,84:705-726.
[128]Hadley RW, Hume JR. An intrinsic potential-dependent inactivation mechanismassociated with calcium channels in guinea-pig myocytes[J]. J Physiol.1987,389:205-222.
[129]Puglisi JL, Yuan W, Bassani JWM, et al. Ca2+influx through Ca2+channels in rabbitventricular myocytes during action potential clamp:Influence of temperature[J].Circ Res.1999,85:7-16.
[130]H6fer GF, Hohenthanner K, Banmgartuer W, et al. Intracellular Ca2+inactivatesL-type Ca2+channels with a Hill coefficient of approximately1and an inhibitionconstant of approximately4gM by reducing channel's open probability[J]. BiophysJ.1997,73:1857-1865.
[131]Zuhlke RD, Reuter I-I. Ca2+sensitive inactivation of L-type Ca2+channels dependson multiple cytoplasmic amino acid sequences of the cqc subunit[J]. Proc Natl AcadSci U S A.1998,95:3287-3294.
[132]Peterson BZ, DeMaria CD, Yue DT. Calmodulin is the Ca2+sensor forCa2+-dependent inactivation of L-type calcium channels[J]. Neuron.1999,22:549-558.
[133]Qin N, Olcese R, Bransby M, et al. Ca2+-induced inhibition of the cardiac CaV1.2channel depends on calmodulin[J]. Proc Nad Acad Sci U S A.1999,96:2435-2438.
[134]Ztihlke RD, Pitt GS, Deisseroth K, et al. Calmodulin supports both inactivation andfacilitation of L-type calcium channels[J]. Nature.1999,399:159-162.
[135]Sipido KR, Callewaert G, Carmeliet E. Inhibition and rapid recovery of Ca2+currentduring Ca2+release from sarcoplasmic reticulum in guinea pig ventricularmyocytes[J]. Circ Res.1995,76:102-109.
[136]January CT, Riddle JM. Early afterdepolarizations:Mechanism of induction andblock. A role for L-type Ca2+current[J]. Circ Res.1989,64:977-990.
[137]Tseng GN. Calcium current restitution in mammalian ventricular myocytes ismodulated by intracellular calcium[J]. Circ Res.1988,63:468-482.
[138]Hryshko LV, Bets DM. Ca2+current fadlitation during post-rest recovery dependson Ca2+entry[J]. Am J Physiol Heart Circ Physiol.1990,259:H951-H961.
[139]Zygmunt AC, Maylie J. Stimulation-dependent facilitation of the high thresholdcalcium current in guinea-pig ventricular myocytes[J]. J Physio.1990,1428:653-67I.
[140]Yuan W, Bers DM. Ca-dependent facilitation of cardiac Ca current is due toCa-calmodulin-dependent protein kinase[J]. Am J Physiol Heart Circ Physiol.1994,267:H982-H993.
[141]Anderson ME, Braun AP, Schulman H, et al. Multifunctonal Ca2+/ealmodulin-ependent protein kinase mediates Ca2+-induced enhancement of the L-type Ca2+current in rabbit ventricular myocytes[J]. Circ Res.1994,75:854-861.
[142]Xiao RP, Cheng H, Lederer WJ, et al. Dual regulation of Ca2+/calmodulin-dependent kinase II activity by membrane vokage and by calcium influx[J]. ProcNad Acad Sci U S A.1994,91:9659-9663.
[143]Dzhnra I, Wu Y, Colbran RJ, et al. Calmodulin kinase determines calcium-dependent facilitation of L-type calcium channels[J]. Nat Cell Biol.2000,2:173-177.
[144]Pietrobon D, Hess P. Modal gating of L-type calcium channels[J]. Biophys J.1990,57:24a.
[145]Sculptoreanu A, Rotman E, Takahashi M, et al. Voltage-dependent potefftiation ofthe activity of cardiac L-type calcium channel al subunits due to phosphorylation bycAMP-dependent protein kinase[J]. Proc Natl Acad Sci U S A.1993,90:10135-10139.
[146]Kamp TJ, Hu H, Marb~n E. Vokage-dependent facilitation of cardiac L-type Cachannels expressed in HEK-293cells requires[J]. Am J Physiol Heart Circ Physiol.2000,278:H126-H136.
[147]Lew WYW, Hryshko LV, Bets DM. Dihydropyridine receptors are primarilyfunctional L-type Ca channels in rabbit cardiac myocytes[J]. Circ Res.1991,69:1139-1145.
[148]Grantham CJ, Cannell MB. Ca2+influx during the cardiac action potential in guineapig ventricular myocytes[J]. Circ Res.1996,79-194-200.
[149]Linz KW, Meyer R. Control of L-type calcium current during the action potential ofguinea-pig ventricular myocytes[J]. J Physiol.1998,513:425--442.
[150]Mikami A, Imoto K, Tanabe T, et al. Primary structure and functional expression ofthe cardiac dihydropyridine-sensitive calcium channel[J]. Nature.1989,340:230-233.
[151]Wakamori M, Mikala G, Schwartz A, et al. Single-channel analysis of a clonedhuman heart L-type Ca2+channel alpha1subunit and the effects of a cardiac betasubunit[J]. Biochem Biophys Res Commun.1993,196:1170-1176.
[152]Yang J, Ellinor PT, Sather WA, et al. Molecular determinants of Ca2+selectivity andion permeation in L-type Ca2+channels[J]. Nature.1993,366:158-161.
[153]Hersel J, Jung S, Mohacsi P, et al. Expression of the L-type calcium channel inhuman heart failure[J]. Basic Res Cardiol.2002,97:I4-10.
[154]Meissner G. Regulation of mammalian ryanodine receptors[J]. Front Biosci.2002,7:2072-2080.
[155]Franzini-Armstrong C, Protasi F. Ryanodine receptors of striated muscles:Acomplex channel capable of multiple interactions[J]. Physiol Rev.1997,77:699-729.
[156]Meissner G. Monovalent ion and calcium ion fluxes in sarcoplasmic reticulum[J].Mol Cell Biochem.1983,55:65-82.
[157]Meissner G. Isolation and characterization of two types of sarcoplasmic reticulumvesicles[J]. Biochim Biophys Acta.1975,389:51-68.
[158]Jones LR, Cala SE. Biochemical evidence for functional heterogeneity of cardiacsarcoplasmic reticulum vesicles[J]. J Biol Chem.1981,256:11809-11818.159]Wier WG, Balke CW. Ca2+release mechanisms, Ca2+sparks, and local control ofexcitation-contraction coupling in normal heart muscle[J]. Circ Res.1999,85:770-776.
[160]Marx SO, Gaburjakova J, Gaburjakova M, et al. Coupled gating between cardiaccalcium release channels(ryanodine receptors)[J]. Circ Res.2001,88:1151-1158.
[161]Gatto C, Hale CC, Xu W, et al. Eosin, a potent inhibitor of the plasma membrane Capump, does not inhibit the cardiac Na-Ca exchanger[J]. Biochemistry.1995,34:965-972.
[162]Choi HS, Eisner DA. The role of sarcolemmal Ca2+-ATPase in the regulation ofresting calcium concentration in rat ventricular myocytes[J]. J Physiol.1999,515:109-118.
[163]Choi HS, Eisner DA. The effects of inhibition of the sarcolemmal Ca2+-ATPase onsystolic calcium fluxes and intracellular calcium concent. ration in rat ventricularmyocytes[J]. Pflugers Arch.1999,437:966-971.
[164]Bers DM. Cardiac excitation-contraction coupling[J]. Nature.2002,415:198-205.
[165]HenaffM, Antoine S, Mercadier JJ, et al. The voltage-independent B-type Ca2+channel modulates apoptosis of cardiac myocytes[J]. FASEB J.2002,16:99-101.
[166]Antoine S, Pinet C, Coulombe A. Are B-type Ca2+channels of cardiac myocytesakin to the passive ion channel in the plasma mem-brane Ca2+pump[J]? J MembrBiol.2001,179:37-50.
[167]Pinet C, Antoine S, Filoteo AG, et al. Reincorporated plasma membraneCa2+-ATPase can mediate B-type Ca2+-channels observed in native membrane ofhuman red blood cells[J]. J Membr Biol.2002,187:185-201.
[168]Philipson KD. Na+-Ca2+exchange:Three new tools[J]. Circ Res.2002,90:118-119.
[169]Carafoli E, Brini M. Calcium pumps:Structural basis for and mechanism of calciumtransmembrane transport[J]. Curr Opin Chem Biol.2000,4:152-161.
[170]Strehler EE, Zacharias DA. Role of alternative splicing in generating isoformdiversity among plasma membrane calcium pumps[J]. Physiol Rev.2001,81:21-50.
[171]Monteith GR, Roufogalis BD. The plasma membrane calcium pumpa physiologicalerspective on its regulation[J]. Cell Calcium.1995,18:459-470.
[172]Penniston JT, Enyedi A. Modulation of the plasma membrane Ca2+pump[J]. JMembr Biol.1998,165:101-109.
[173]Takeshima H, Ikemoto T, Nishi M, et al. Generation and characterization of mutantmice lacking ryanodine receptor type3[J]. J Biol Chem.1996,271:19649-19652.
[174]Takeshima H, Komazaki S, Hirose K, et al. Embryonic lethality and abnormalcardiac myocytes in mice lacking ryanodine receptor type2[J]. EMBOJ.1998,17:3309-3316.
[175]Anderson K, Lai FA, Liu QY, et al. Structural and functional charac terization of thepurified cardiac ryanodine receptor-Ca2+release channel complex[J]. J Biol Chem.1989,264:1329-1335.
[176]Sharma MR, Penczek P, Grassucci R, et al. Cryoelectron microscopy and imageanalysis of the cardiac ryanodine receptor[J]. J Biol Chem.1998,273:18429-18434.
[177]Du GG, Sandhu B, Khanna VK, et al. Topology of the Ca2+release channel ofskeletal muscle sarcoplasmic reticulum(RyR1)[J]. Proc Nad Acad Sci USA.2002,99:16725-6730.
[178]Tinker A, Lindsay AR, Williams AJ. Cation conduction in the calcium releasechannel of the cardiac sarcoplasmic reticulum under physiological and pathophysiological conditions[J]. Cardiovasc Res.1993,27:1820-1825.
[179]Chen DP, Xu L, Tripathy A, et al. Selectivity and permeation in calcium releasechannel of cardiac muscle:Alkali metal ions[J]. Biophys J.1999,76:1346-1366.
[180]MacKrill JJ. Protein-protein interactions in intracellular Ca2+release channelfunction[J]. Biochem J.1999,337:345-361.
[181]Marks AR. Ryanodine receptors, FKBP12, and heart failure[J]. Front Biosci.2002,7:970-977.
[182]Xu L, Meissner G. Regulation of cardiac muscle Ca2+release channel bysarcoplasmic reticulum lumenal Ca2+[J]. Biophys J.1998,75:2302-2312.
[183]Sitsapesan R, Williams AJ. Regulation of current flow through ryanodine receptorsby luminal Ca2+[J]. J Membr Biol.1997,159:179-185.
[184]Nunogaki K, Kasai M. Determination of the rate of rapid pH equilibration acrossisolated sarcoplasmic reticulum membranes[J]. Biochem Biophys Res Comm.1986,140:934-940.
[185]Anderson ME. Calmodulin and the Philosopher's stone:Changing Ca2+intoarrhythmias[J]. J Cardiovasc Electrophysiol.2002,13:195-197.
[186]Balshaw DM, Yamaguchi N, Meissner G. Modulation of intracellular calciumrelease channels by calmodulin[J]. J Membr Biol.2002,185:1-8.
[187]Yamaguchi N, Xin C, Meissner G. IdentifiCation of apocalmodulin and Ca2+calmodulin regulatory domain in skeletal muscle Ca2+release channel, ryanodinereceptor[J]. J Biol Chem.2001,276:22579-22585.
[188]Eu JP, Sun J, Xu L. The skeletal muscle calcium release channel:Coupled02sensorand NO signaling functions[J]. Cell.2000,102:499-509.
[189]Xu L, Eu JP, Meissner G, et al. Activation of the cardiac calcium releasechannel(ryanodine receptor)by poly-S-nitrosylation[J]. Science.1998,279:234-237.
[190]Eu JP, Xu L, Stamler JS, et al. Regulation of ryanodine receptors by reactivenitrogen species[J]. Biochem Pharmacol.1999,57:1079-1084.
[191]Ziolo MT, Katoh H, Bers DM. Positive and negative effects of nitric oxide on Ca2+sparks:Influence of beta adrenergic stimulation[J]. Am J Physiol.2001,281:2295-H2303.
[192]PetroffMG, Kim SH, Pepe S, et al. Endogenous nitric oxide mechanisms mediatethe stretch dependence of Ca2+release in cardiomyocytes[J]. Nature Cell Biol.2001,3:867-873.
[193]Sun J, Xu L, EuJP, et al. Nitric oxide, NOC-12and S-nitrosoglu-tathione modulatethe skeletal muscle calcium release ehannel/ryan-odine receptor by differentmechanisms:An allosteric function for02in S-nitrosylation of the channel[J]. J BiolChem.2003,278:8184-8189.
[194]Marx S, Reiken S, Hisamatsu Y, et al. Phosphorylation-dependent regulation ofryanodine receptors:A novel role for leucine/isoleucine zippers[J]. J Cell Biol.2001,153:699-708.
[195]Marx S, Reiken S, Hisamatsu Y, et al. PKA phosphorylation dissociates FKBP12.6from the calcium release channel(ryanodine receptor):Defective regulation infailing hearts[J]. Cell2000;101:365-376.
[196]Bosch RF, Nattel S. Cellular electrophysiology of atrial fibrillation[J]. CardiovascRes.2002,54:259-69.
[197]Verheule S, Wilson E, Banthia S, et al. Direction-dependent conduction abnormallities in a canine model of atrial fibrillation due to chronic atrial dilatation[J]. Am JPhysiol Heart Circ Physiol.2004,287:H634-44.
[198]Willems R, Holemans P, Ector H, et al. Mind the model:effect of instrumentationon inducibility of atrial fibrillation in a sheep model[J]. J Cardiovasc Electrophysiol.2002,13:62-67.
[199]Nattel S, Khairy P, Schram G. Arrhythmogenic ionic remodelling:adaptiveresponses with maladaptive consequences[J]. Trends Cardiovasc Med.2001,11:295-301.
[200]Baba S, Dun W, Hirose M, et al. Sodium current function in adult and aged canineatrial cells[J]. Am J Physiol Heart Circ Physiol.2006,291:H756-H761.
[201]King LM, Opie LH. Glucose and glycogen utilisation in myocardialischemia-changes in metabolism and consequences for the myocyte[J]. Mol CellBiochem.1998,180:3-26.
[202]O’Rourke B, Ramza BM, Marban E. Oscillations of membrane current andexcitability driven by metabolic oscillations in heart cells[J]. Science.1994,265:62-966.
[203]Depre C, Rider M, Hue L. Mechanisms of control of heart glycolysis[J]. Eur JBiochem.1998,258:277-290.
[204]Cortassa S, Aon MA, Marban E, et al. An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics[J]. Biophys J.2003,84:2734-2755,.
[205]Mihm MJ, Yu F, Carnes CA, et al. Impaired myofibrillar energetics and oxidativeinjury during human atrial fibrillation[J]. Circulation.2001,104:174-180.
[206]Strand MA, Louis CF, Mickelson JR. Phosphorylation of porcine skeletal andcardiac muscle sarcoplasmic reticulum ryanodine receptor[J]. Biochim BiophysActa.1993,1175:319-326.
[207]Witcher DR, Kovacs RJ, Schulman H, et al. Unique phosphoration site on thecardiac ryanodine receptor regulates calcium channel activity[J]. J Biol Chem.1991,266:11144-11152.
[208]Hain J, Onoue H, Mayrleitner M, et al. Phosphorylation modulates the function ofthe calcium release channel of sarcoplasmic reticulum from cardiac muscle[J]. JBiol Chem.1995,270:2074-2081.
[209]Eisner DA, Diaz ME, Li Y, et al. Stability and instability of regulation ofintracellular calcium[J]. Exp Physiol.2005,90:3-12.
[210]Katra RP, Laurita KR. Cellular mechanism of calcium-mediated triggered activityin the heart[J]. Circ Res.2005,96:535-542.
[211]Croall DE, DeMartino GN. Calcium-activated neutral protease (calpain)system:structure, function, and regulation[J]. Physiol Rev.1991,71:813-847.
[212]Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodelingduring atrial fibrillation[J]. Cardiovasc Res.2002,54:230-246.
[213]Bers DM. Calcium cycling and signaling in cardiac myocytes[J]. Annu Rev Physiol.2008,70:23-49.
[214]Sorimachi H, Ishiura S, Suzuki K. Structure and physiological function ofcalpains[J]. Biochem J.1997,328(Pt3):721-732.
[215]Saido TC, Sorimachi H, Suzuki K. Calpain:New perspectives in molecular diversityand physiological-pathological involvement[J]. FASEB J.1994,8:814-822.
[216]Carafoli E, Molinari M. Calpain:A protease in search of a function[J]? BiochemBiophys Res Commun.1998,247:193-203.
[217]Sorimachi H, Suzuki K. The structure of calpain[J]. J Biochem.2001,129:653-664.
[218]Huang Y, Wang KK. The calpain family and human disease[J]. Trends Mol Med.2001,7:355-362
[219]Guroff G. A neutral calcium-activated proteinase from the soluble fraction of ratbrain[J]. J Biol Chem.1964,239:149-155.
[220]Meyer WL, Fischer EH, Krebs EG. Activation of skeletal muscle phosphorylase bkinase by Ca2+[J]. Biochemistry.1964,3:1033-1039.
[221]Busch WA, Stromer MH, Goll DE, et al. Ca2+-specific removal of Z lines fromrabbit skeletal muscle[J]. J Cell Biol.1972,52:367-381.
[222]Takai Y, Yamamoto M, Inoue M, et al. A proenzyme of cyclicnucleotide-independent protein kinase and its activation by calcium-dependentneutral protease from rat liver[J]. Biochem Biophys Res Commun.1977,77:542-550.
[223]Ishiura S, Murofushi H, Suzuki K, et al. Studies of a calcium-activated neutralprotease from chicken skeletal muscle:Purification and characterization[J]. JBiochem.1978,84:225-230.
[224]Suzuk K. Nomenclature of calcium dependent proteinase[J]. Biomed Biochim Acta.1991,50:483-484.
[225]Goll DE, Thompson VF, Li H, et al. The calpain system[J]. Physiol Rev.2003,83:731-801.
[226]Melloni E, Michetti M, Salamino F, et al. Molecular and functional properties of acalpain activator protein specific for mu-isoforms[J]. J Biol Chem.1998,273:12827-12831.
[227]Suzuki K, Hata S, Kawabata Y, et al. Structure, activation, and biology of calpain[J].Diabetes.2004,53(Suppl1):S12-S18.
[228]Croall DE, Demartino GN. Calcium-activated neutral protease (calpain) system:Structure, function, and regulation[J]. Physiol Rev.1991,71:813-847.
[229]Moldoveanu T, Campbell RL, Cuerrier D, et al. Crystal structures of calpain-E64and-leupeptin inhibitor complexes reveal mobile loops gating the active site[J]. JMol Biol.2004,343:1313-1326.
[230]Reverter D, Strobl S, Fernandez-Catalan C, et al. Structural basis for possiblecalcium-induced activation mechanisms of calpains[J]. Biol Chem.2001,382:753-766.
[231]Tompa P, Emori Y, Sorimachi H, et al. Domain III of calpain is a Ca2+-regulatedphospholipid-binding domain[J]. Biochem Biophys Res Commun.2001,280:1333-1339.
[232]Minami Y, Emori Y, Imajoh-Ohmi S, et al. Carboxyl-terminal truncation andsite-directed mutagenesis of the EF hand structure-domain of the small subunit ofrabbit calcium-dependent protease[J]. J Biochem.1988,104:927-933.
[233]Hosfield CM, Elce JS, Davies PL, et al. Crystal structure of calpain reveals thestructural basis for Ca2+-dependent protease activity and a novel mode of enzymeactivation[J]. EMBO J.1999,18:6880-6889.
[234]Lin GD, Chattopadhyay D, Maki M, et al. Crystal structure of calcium bounddomain VI of calpain at1.9A resolution and its role in enzyme assembly,regulation, and inhibitor binding[J]. Nat Struct Biol.1997,4:539-547.
[235]Ozaki T, Tomita H, Tamai M, et al. Characteristics of mitochondrial calpains[J]. JBiochem.2007,142:365-376.
[236]Kar P, Samanta K, Shaikh S, et al. Mitochondrial calpain system:An overview[J].Arch Biochem Biophys.2010,495:1-7.
[237]Moldoveanu T, Hosfield CM, Lim D, et al. A Ca2+switch aligns the active site ofcalpain[J]. Cell2002;108:649-660.
[238]Nakagawa K, Masumoto H, Sorimachi H et al. Dissociation of m-calpain subunitsoccurs after autolysis of the N-terminus of the catalytic subunit, and is not requiredfor activation[J]. J Biochem.2001,130:605-611.
[239]Suzuki K, Sorimachi H, Yoshizawa T et al. Calpain:Novel family members,activation, and physiological function[J]. Biol Chem Hoppe-Seyler.1995,376:523-529.
[240]Chakrabarti AK, Dasgupta S, Gadsden RH Sr et al. Regulation of brain m calpainCa2+sensitivity by mixtures of membrane lipids:Activation at intracellular Ca2+level[J]. J Neurosci Res.1996,44:374-380.
[241]Wendt A, Thompson VF, Goll DE. Interaction of calpastatin with calpain[J]. BiolChem.2004,385:465-472.
[242]Zhang L, Ma B, Wu J, et al. Cloning and characterization of the yak gene coding forcalpastatin and in silico analysis of its putative product[J]. Acta Biochim Pol.2010,57:35-41.
[243]Sorimachi H, Kimura S, Kinbara K, et al. Muscle-specific calpain, p94, responsiblefor limb girdle muscular dystrophy type2A, associates with connectin through IS2,a p94-specific sequence[J]. J Biol Chem.1995,270:31158-31162.
[244]Shiraha H, Glading A, Chou J, et al. Activation of m-calpain(calpain II)byepidermal growth factor is limited by protein kinase A phosphorylation ofm-calpain[J]. Mol Cell Biol.2002,22:2716-2727.
[245]A. M. Cuervo and J. F. Dice, Age-related decline in chaperone-mediatedautophagy[J]. J. Biol. Chem.2000,275:31505-31513.
[246]M. Baudry, R. DuBrin, L. Beasley, M. et al. Lynch, Low levels of calpain activity inChiroptera brain:implications for mechanisms of aging[J]. Neurobiol.1986,7:255-258.
[247]E. M. Blalock, N. M. Porter and P. W. Landfield, Decreased G-protein-mediatedregulation and shift in calcium channel types with age in hippocampal cultures[J]. J.Neurosci.1999,19:8674-8684.
[248]H. Manya, M. Inomata, T. Fujimori, M. et al. Nabeshima and T. Endo, Klothoprotein deficiency leads to overactivation of mu-calpain[J]. J. Biol. Chem.2002,277:5503-5508.
[249]L. L. David, J. W. Wright and T. R. Shearer, Calpain II induced insolubilization oflens beta-crystallin polypeptides may induce cataract[J]. Biochim. Biophys. Acta.1992,1139:210-216.
[250]M. J. Kelley, L. L. David, N. Iwasaki, M. et al. Shearer, Alpha-crystallin chaperoneactivity is reduced by calpain II in vitro and in selenite cataract[J]. J. Biol. Chem.1993,268:18844-18849.
[251]M. Kuro-o, Y. Matsumura, H. Aizawa,, M. et al. Nabeshima, Mutation of the mouseklotho gene leads to a syndrome resembling ageing[J]. Nature.1997,390:45-51.
[252]H. Manya, M. Inomata, T. Fujimori, N. M. et al. Nabeshima and T. Endo, Klothoprotein deficiency leads to overactivation of mu-calpain[J]. J. Biol. Chem.2002,277:5503-5508.
[253]M. Averna, R. De Tullio, F. Salamino, R. M. et al. Age-dependent degradation ofcalpastatin in kidney of hypertensive rats[J]. J. Biol. Chem.2001,276:38426-38432.
[254]Goette A, Arndt M, R cken C, et al. Calpains and cytokines in fibrillating humanatria[J]. Am J Physiol Heart Circ Physiol.2002,283:H264-H272.
[255]Bukowska A, Lendeckel U, Hirte D, et al. Activation of the calcineurin signalingpathway induces atrial hypertrophy during atrial fibrillation[J]. Cell Mol Life Sci.2006,63:333-342.
[256]Qi XY, Yeh YH, Xiao L, et al. Cellular signaling underlying atrial tachycardiaremodeling of L-type calcium current[J]. Circ Res.2008,103:845-854.
[257]Jayachandran JV, Zipes DP, Weksler J, M. et al. Role of the Na+/H+exchanger inshort-term atrial electrophysiological remodeling[J]. Circulation.2000,101:1861-1866.
[258]Chen M, Won DJ, Krajewski S, M. et al. Calpain and mitochondria inischemia/reperfusion injury[J]. J Biol Chem.2002,277:29181-29186.
[259]Everett TH, Li H, Mangrum JM, et al. Electrical, morphological, and ultrastruc turalremodeling and reverse remodeling in a canine model of chronic atrialfibrillation[J]. Circulation.2000,102:1454-1460.
[260]Fatkin D, Kuchar DL, Thorburn CW, M. et al. Transesophageal echocar diographybefore and during direct current cardioversion of atrial fibrillation:Evidence foratrial stunning as a mechanism of thrombembolic complications[J]. J Am CollCardiol.1994,23:307-316.
[261]Sanfilippo AJ, Abascal VM, Sheehan M, M. et al. Atrial enlargement as aconsequence of atrial fibrillation. A prospective echocardiographic study[J].Circulation.1990,82:792-797.
[262]Schotten U, Ausma J, Stellbrink C, et al. Cellular mechanisms of depressed atrialcontractility in patients with chronic atrial fibrillation[J]. Circulation.2001,103:691-698.
[263]Schotten U, Greiser M, Benke D, et al. Atrial fibrillation-induced atrial contractiledysfunction:A tachycardiomyopathy of a different sort[J]. Cardiovasc Res.2002,53:192-201.
[264]Arndt M, Lendeckel U, R cken C, et al. Altered expression of ADAMs infibrillating atria[J]. Circulation.2002,105:720-725.
[265]Li Y, Gong ZH, Sheng L, et al. Anti-apoptotic effects of a calpain inhibitor oncardiomyocytes in a canine rapid atrial fibrillation model[J]. Cardiovasc Drugs Ther.2009,23:361-368.
[266]Gafni J, Cong X, Chen SF, M. et al. Calpain-1cleaves and activates caspase-7[J]. JBiol Chem.2009,284:25441-25449.
[267]Choudhury S, Bae S, Kumar SR, et al. Role of AIF in cardiac apoptosis inhypertrophic cardiomyocytes from Dahl salt-sensitive rats[J]. Cardiovasc Res.2010,85:28-37.
[268]Norberg E, Gogvadze V, Ott M, M. et al. An increase in intracellular Ca2+isrequired for the activation of mitochondrial calpain to release AIF during celldeath[J]. Cell Death Differ.2008,15:1857-1864.
[269]Crompton M. The mitochondrial permeability transition pore and its role in celldeath[J]. Biochem J.1999,341:233-249.
[270]Di Lisa F, Menabò R, Canton M, et al. Opening of the mitochondrial permeabilitytransition pore causes depletion of mitochondrial and cytosolic NAD+and is acausative event in the death of myocytes in postischemic reperfusion of the heart[J].J Biol Chem.2001,276:2571-2575.
[271]Goette A, Bukowska A, Dobrev D, et al. Acute atrial tachyarrhythmia inducesangiotensin II type1receptor-mediated oxidative stress and microvascular flowabnormalities in the ventricles[J]. Eur Heart J.2009,30:1411-1420.
[272]Bukowska ASL, Keilhoff G, Hirte D, et al. Mitochondrial dysfunction and redoxsignaling in atrial tachyarrhythmia[J]. Exp Biol Med(Maywood).2008,233:558-574.
[273]Murata M, Akao M, O’Rourke B, et al. Mitochondrial m-calpain plays a role in therelease of truncated apoptosis-inducing factor from the mitochondria[J]. BiochimBiophys Acta.2009,1793:1848-1859.
[274]Arrington DD, Van Vleet TR, Schnellmann RG. Calpain10:A mitochondrial calpainand its role in calcium-induced mitochondrial dysfunction[J]. Am J Physiol CellPhysiol.2006,291:C1159-C1171.
[275]Kar P, Chakraborti T, Samanta K, et al. mu-Calpain mediated cleavage of theNa+/Ca2+exchanger in isolated mitochondria under A23187induced Ca2+stimulation[J]. Arch Biochem Biophys.2009,482:67-76.
[276]Lockshin RA, Facey CO, Zakeri Z. Cell death in the heart[J]. Cardiol Clin.2001,19:1-11.
[277]Reijonen S, Kukkonen JP, Hyrskyluoto A, et al. Downregulation of NF-kappaBsignaling by mutant huntingtin proteins induces oxidative stress and cell death[J].Cell Mol Life Sci.2010,67:1929-1941.
[278]Eckstein J, Verheule S, de Groot NM, et al. Mechanisms of perpetuation of atrialfibrillation in chronically dilated atria. Prog Biophys Mol Biol.2008;97:435-51.
[279]Verheule S, Sato T, Everett Tt, et al. Increased vulnerability to atrial fibrillation intransgenic mice with selective atrial fibrosis caused by overexpression ofTGF-beta1[J]. Circ Res.2004,94:1458-65.
[280]Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosisand renin-angiotensin-aldosterone system[J]. Circulation.1991,83:1849-65.
[281]Yang SS, Han W, Zhou HY, et al. Effects of spironolactone on electrical andstructural remodeling of atrium in congestive heart failure dogs[J]. Chin MedJ(Engl)2008,121:38-42.
[282]Beltrami CA, Finato N, Rocco M, et al. The cellular basis of dilatedcardiomyopathy in humans[J]. J Mol Cell Cardiol.1995,27:291-305.
[283]Rakusan K, Flanagan MF, Geva T, et al. Morphometry of human coronarycapillaries during normal growth and the effect of age in left ventricularpressure-overload hypertrophy[J]. Circulation.1992,86:38-46.
[284]Sharov VG, Sabbah HN, Shimoyama H, et al. Evidence of cardiocyte apoptosis inmyocardium of dogs with chronic heart failure[J]. Am J Pathol.1996,148:141-149.
[285]Arends MJ, Morris RG, Wyllie AH. Apoptosis:the role of endonuclease[J]. Am JPathol.1990,136:593-608.
[286]Krajewski S, Krajewska M, Shabaik A, et al. Immunohistochemical determinationof in vivo distribution of Bax, a dominant inhibitor of Bcl-2[J]. Am J Pathol.1994,145:1323-1336
[287]Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases:influence on cardiac form and function[J]. Physiol Rev.2007,87:1285-342.
[288]Remes J, van Brakel TJ, Bolotin G, et al. Persistent atrial fibrillation in a goat modelof chronic left atrial overload[J]. J Thorac Cardiovasc Surg.2008,136:1005-11.
[289]Knackstedt C, Gramley F, Schimpf T, et al. Association of echocardiographic atrialsize and atrial fibrosis in a sequential model of congestive heart failure and atrialfibrillation[J]. Cardiovasc Pathol.2008,17:318-24.
[290]Kassiri Z, Khokha R. Myocardial extra-cellular matrix and its regulation bymetalloproteinases and their inhibitors[J]. Thromb Haemost.2005,93:212-9.
[291]Herpel E, Pritsch M, Koch A, et al. Interstitial fibrosis in the heart:differences inextracellular matrix proteins and matrix metalloproteinases in end-stage dilated,ischaemic and valvular cardiomyopathy[J]. Histopathology.2006,48:736-47.
[292]Cardin S, Libby E, Pelletier P, et al. Contrasting gene expression profiles in twocanine models of atrial fibrillation[J]. Circ Res.2007,100:425-33.
[293]Bouzeghrane F, Reinhardt DP, Reudelhuber TL, et al. Enhanced expression offibrillin-1, a constituent of the myocardial extracellular matrix in fibrosis[J]. Am JPhysiol Heart Circ Physiol.2005,289:H982-91.
[294]Lin CS, Lai LP, Lin JL, et al. Increased expression of extracellular matrix proteinsin rapid atrial pacing-induced atrial fibrillation[J]. Heart Rhythm.2007,4:938-49.
[295]Ramirez F, Rifkin DB. Extracellular microfibrils:contextual platforms for TGF betaand BMP signaling[J]. Curr Opin Cell Biol.2009,8:42-47.
[296]Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases:influence on cardiac form and function[J]. Physiol Rev.2007,87:1285-342.
[297]Mukherjee R, Herron AR, Lowry AS, et al. Selective induction of matrixmetalloproteinases and tissue inhibitor of metalloproteinases in atrial andventricular myocardium in patients with atrial fibrillation[J]. Am J Cardiol.2006,97:532-7.
[298]Moe GW, Laurent G, Doumanovskaia L, et al. Matrix metalloproteinase inhibitionattenuates atrial remodeling and vulnerability to atrial fibrillation in a canine modelof heart failure[J]. J Card Fail.2008,14:768-76.
[299]MacLellan W, Schneider M. Death by design. Programmed cell death incardiovascular biology and disease[J]. Circ Res.1997,81:137-144.
[300]Haunstetter A., Izumo S. Apoptosis:Basic mechanism and implication forcardiovascular disease[J]. Circ Res.1998,82:1111-1129.
[301]Olivetti G, Abbi R, Quaini F, et al. Apoptosis in human failing heart[J]. New Engl JMed.1997,336:1131-1141.
[302]Doggrell S, Brown L. Rat models of hypertension, cardiac hypertrophy andfailure[J]. Cardiovasc Res.1998,39:89-105.
[303]Adams J, Sakata Y, Davis M, et al. Enhanced Gαq signaling:a common pathwaymediates cardiac hypertrophy and apoptotic heart failure[J]. Proc Natl Acad SciUSA.1998,95:10140-10145.
[304]Wang Y, Huang S, Sah V, et al. Cardiac muscle cell hypertrophy and apoptosisinduced by distinct members of the p38mitogen-activated protein kinase family[J].J Biol Chem.1998,273:2161-2168.
[305]Wang Y, Su B, Sah V, et al. Cardiac hypertrophy induced by mitogen-activatedprotein kinase kinase7, a specific activator of c-jun NH2-terminal kinase inventricular muscle cells[J]. J Biol Chem.1998,273:5423-5426.
[306]Srivastava R, Sollott S, Khna L, et al. Bcl-2and Bcl-XLblock thapsigargin-inducednitric oxide generation, c-Jun NH2-terminal kinase activity, and apoptosis. Mol CellBiol[J].1999,19:5659-5674.
[307]Aikawa R, Komuro I, Yamazaki T, et al. Oxidative stress activates extracellularsignal-regulated kinases through Src and Ras in cultured cardiac myocytes ofneonatal rats[J]. J Clin Invest.1997,100:1813-1821.
[308]Krown K, Page M, Nguyen C, et al. Tumor necrosis factor-alpha-induced apoptosisin cardiac myocytes[J]. J Clin Invest.1996,98:2854-2865.
[309]Clerk A, Sugden P. Mitogen-activated protein kinases are activated by oxidativestress and cytokines in neonatal ventricular myocytes[J]. Biochem Soc Trans.1997,25:566S.
[310]Adderley S, Fitzgerald D. Oxidative damage of cardiomyocytes is limited byextracellular-regulated kinases1/2-mediated induction of cyclooxygenase-2[J]. JBiol Chem.1999,274:5038-5046.
[311]Erhardt P, Schremser E, Cooper G. B-Raf inhibits programmed cell deathdownstream of cytochrome c release from mitochondria by activating theMEK/ERK pathway[J]. Mol Cell Biol.1999,19:5308-5315.
[312]Kennedy S, Kandel E, Cross T, et al. Akt/protein kinase B inhibits cell death bypreventing the release of cytochrome c from mitochondria[J]. Mol Cell Biol.1999,19:5800-5810.
[313]Molkentin J, Lu J, Antos C, et al. A calcineurin-dependent transcriptional pathwayfor cardiac hypertrophy[J]. Cell.1998;93:215-228.
[314]Uemura A, Naito Y, Matsubara T, et al. Demonstration of a Ca2+/calmodulindependent protein kinase cascade in the hog heart[J]. Biochem Biophys ResCommun.1998;249:355-360.
[315]Cardone M, Roy N. H. R. S, Stennicke H. R, et al. Regulation of cell death proteasecaspase-9by phosphorylation[J]. Science.1998,282:1318-1321.
[316]Narula J, Pandey P, Arbustini E, et al. Apoptosis in heart failure:release ofcytochrome c from mitochondria and activation of caspase-3in humancardiomyopathy[J]. Proc Natl Acad Sci USA.1999,96:8144-8149.
[317]Saikumar P, Dong Z, Weinberg J, et al. Mechanisms of cell death inhypoxia/reoxygenation injury[J]. Oncogene.1998,17:3341-3349.
[318]Berridge M, Tan A, McCoy K, et al. CD95(Fas/Apo-1)-induced apoptosis results inloss of glucose transporter function[J]. J Immunol.1996,156:4092-4099.
[319]Marton A, Mihalik R, Bratincsak A, et al. Apoptotic cell death induced byinhibitors of energy conservation[J]. Eur J Biochem.1997,250:467-475.
[320]Kirshenbaum L, de Moissac D. The bcl-2gene product prevents programmed celldeath of ventricular myocytes[J]. Circulation.1997,96:1580-1585.
[321]Garland J, Halestrap A. Energy metabolism during apoptosis:Bcl-2promotes cellsurvival in hematopoietic cells induced to apoptose by growth factor withdrawal bystabilizing a form of metabolic arrest[J]. J Biol Chem.1997,272:4680-4688.
[322]Taimor G, Lorenz H, Hofstaetter B, et al. Induction of necrosis but not apoptosisafter anoxia and reoxygenation in isolated adult cardiomyocytes of rat[J].Cardiovasc Res.1999,41:147-156.
[323]Olivetti G, Abbi R, Quaini F, et al. Apoptosis in the failing human heart[J]. N Engl JMed.1997,336(16):1131-41.
[324]Colucci WS. Apoptosis in the heart[J]. N Engl J Med.1996,335:1224-1226.
[325]Benjamin IJ, Jalil JE, Tan LB, et al. Isoproterenol-induced myocardial fibrosis inrelation to myocyte necrosis[J]. Circ Res.1989,65:657-670.
[326]orczyca W, Gong J, Darzynkiewicz Z. Detection of DNA strand breaks inindividual apoptotic cells by the in situ terminal deoxynucleotidyl transferase andnick translation assays[J]. Cancer Res.1993,53:1945-1951.
[327]Oberhammer F, Wilson JW, Dive C, et al. Structural basis of end-stage failure inischemic cardiomyopathy in humans[J]. Circulation.1994,89:151-163.
[329]Tanaka M, Ito H, Adachi S, et al. Hypoxia induces apoptosis with enhancedexpression of Fas antigen messenger RNA in cultured neonatal ratcardiomyocytes[J]. Circ Res.1994,75:426-433.
[330]Buerke M, Murohara T, Skurk C, et al. Cardioprotective effect of insulin-likegrowth factor I in myocardial ischemia followed by reperfusion[J]. Proc Natl AcadSci U S A.1995,92:8031-8035.
[331]James TN, St Martin E, Willis PW III, et al. Apoptosis as a possible cause ofgradual development of complete heart block and fatal arrhythmias associated withabsence of the AV node, sinus node, and internodal pathways[J]. Circulation.1996,93:1424-1438.
[332]Itoh G, Tamura J, Suzuki M, et al. DNA fragmentation of human infarctedmyocardial cells demonstrated by the nick end labeling method and DNA agarosegel electrophoresis[J]. Am J Pathol.1995,146:1325-1331.
[333]Cannon PJ, Weiss MB, Sciacca RR. Myocardial blood flow in coronary arterydisease:studies at rest and during stress with inert gas washout techniques[J]. ProgCardiovasc Dis.1977,20:95-120.
[334]Zha HB, Aime-Sempe C, Sato T, et al. Proapoptotic protein Bax heterodim-izeswith Bcl-2and homodimerizes with Bax via a novel domain(BH3)distinct fromBH1and BH2[J]. J Biol Chem.1996,271:7440-7444.
[335]Disertori M, Latini R, Barlera S, et al. Valsartan for prevention of recurrent atrialfibrillation[J]. N Engl J Med.2009,360:1606-17.
[336]Cardin S, Libby E, Pelletier P, et al. Contrasting gene expression profiles in twocanine models of atrial fibrillation[J]. Circ Res.2007,100:425-33.
[337]Mukherjee R, Herron AR, Lowry AS, et al. Selective induction of matrixmetalloproteinases and tissue inhibitor of metalloproteinases in atrial andventricular myocardium in patients with atrial fibrillation[J]. Am J Cardiol.2006,97:532-7.
[338]Lin CS, Lai LP, Lin JL, et al. Increased expression of extracellular matrix proteinsin rapid atrial pacing-induced atrial fibrillation[J]. Heart Rhythm.2007,4:938-49.
[339]Moe GW, Laurent G, Doumanovskaia L, et al. Matrix metalloproteinase inhibitionattenuates atrial remodeling and vulnerability to atrial fibrillation in a canine modelof heart failure[J]. J Card Fail.2008,14:768-76.
[340]Tanaka K, Zlochiver S, Vikstrom KL, et al. The spatial distribution of fibrosisgoverns fibrillation wave dynamics in the posterior left atrium during heartfailure[J]. Circ Res.2007,101:839-847.
[341]Goodwin G, Taylor C, Taegtmeyer H. Regulation of energy metabolism of the heartduring acute increase in heart work[J]. J Biol Chem.1998,273:29530-29539.
[342]Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2heterodimerizes in vivo with aconserved homolog, bax, that accelerates programed cell death[J]. Cell.1993,74:609-619.
[343]X. M. Yin, Z. N. Oltvai and S. J. Korsmeyer. BH1and BH2domains of bcl-2arerequired for inhibition of apoptosis and heterodimerization with Bax[J]. Nature.1994;369:321-333.
[344]Van Bilsen M, Van der Vusse G, Reneman R. Transcriptional regulation ofmetabolic processes:implications for cardiac metabolism[J]. Pflügers Arch.1998,437:2-14.
[345]Marton A, Mihalik R, Bratincsák A, et al. Apoptotic cell death induced byinhibitors of energy conservation[J]. Eur J Biochem.1997,250:467-475.
[346]Cheng EH, Kirsch DG, Clem RJ, et al. Conversion of Bcl-2to a Bax-like deatheffector by caspases[J]. Science.1997,278:1966-8.
[347]Boehm M, Slack F. A developmental timing microRNA and its target regulate lifespan in C. elegans[J]. Science.2005,310:1954-1957.
[348]Chen LH, Chiou GY, Chen YW, et al. MicroRNA and aging:a novel modulator inregulating the aging network[J]. Ageing Res. Rev.2010,9(Suppl1):S59-S66.
[349]Grillari J, Grillari-Voglauer R. Novel modulators of senescence, aging, andlongevity:small non-coding RNAs enter the stage[J]. Exp. Gerontol.2010,45:302-311.
[350]Ikeda S, Kong SW, Lu J, et al. Altered microRNA expression in human heartdisease[J]. Physiol Genomics.2007,31:367-373.
[351]van Rooij E, Sutherland LB, Liu N, et al. A signature pattern of stress-responsivemicroRNAs that can evoke cardiac hypertrophy and heart failure[J]. Proc Natl AcadSci USA.2006,103(48):18255-18260.
[352]Sayed D, Hong C, Chen IY, et al. MicroRNAs play an essential role in thedevelopment of cardiac hypertrophy[J]. Circ Res.2007,100(3):416-424.
[353]Cheng YH, Ji RR, Yue JM, et al. MicroRNAs are aberrantly expressed inhypertrophic heart-do they play a role in cardiac hypertrophy[J]? Am J Pathol.2007;170(6):1831-1840.
[354]Tatsuguchi M, Seok HY, Callis TE, et al. Expression of microRNAs is dynamicallyregulated during cardiomyocyte hypertrophy[J]. J Mol Cell Cardiol.2007,42(6):1137-1141.
[355]van Rooij E, Sutherland LB, Thatcher JE, et al. Dysregulation of microRNAs aftermyocardial infarction reveals a role of miR-29in cardiac fibrosis[J]. Proc Natl AcadSci USA.2008,105:13027-13032.
[356]Roy S, Khanna S, Hussain SR, et al. MicroRNA expression in response to murinemyocardial infarction:miR-21regulates fibroblast metalloprotease-2viaphosphatase and tensin homologue[J]. Cardiovasc Res.2009,82(1):21-29.
[357]Care A, Catalucci D, Felicetti F, et al. MicroRNA-133controls cardiachypertrophy[J]. Nat Med.2007,13(5):613-618.
[358]Matkovich SJ, van Booven DJ, Youker KA, et al. Reciprocal regulation ofmyocardial microRNAs and messenger RNA in human cardiomyopathy andreversal of the microRNA signature by biomechanical support[J]. Circulation.2009,119(9):1263-1271.
[359]Naga Prasad SV, Duan ZH, Gupta MK, et al. A unique microRNA profile inend-stage heart failure indicates alterations in specific cardiovascular signalingnetworks[J]. J Biol Chem.2009,284:27487-27499.
[360]Sucharov C, Bristow MR, Port JD. miRNA expression in the failing humanheart:functional correlates[J]. J Mol Cell Cardiol.2008,45(2):185-192.
[361]Ikeda S, Kong SW, Lu J, et al. Altered microRNA expression in human heartdisease[J]. Physiol Genomics.2007,31(3):367-373.
[362]Thum T, Galuppo P, Wolf C, et al. MicroRNAs in the human heart-a clue to fetalgene reprogramming in heart failure[J]. Circulation.2007,116(3):258-267.
[363]Morin RD, O’Connor MD, Griffith M, et al. Application of massively parallelsequencing to microRNA profiling and discovery in human embryonic stem cells[J].Genome Res.2008,18(4):610-621.
[364]Willenbrock H, Salomon J, Sokilde R, et al. Quantitative miRNA expressionanalysis:comparing microarrays with next-generation sequencing[J]. RNA.2009,15(11):2028-2034.
[365]Cheng Y, Liu X, Zhang S, et al. MicroRNA-21protects against the H2O2-inducedinjury on cardiac myocytes via its target gene PDCD4[J]. J Mol Cell Cardiol.2009,47(1):5-14.
[366]Xu C, Lu Y, Pan Z, et al. The muscle-specific microRNAs miR-1and miR-133produce opposing effects on apoptosis by targeting HSP60, HSP70and caspase-9incardiomyocytes[J]. J Cell Sci.2007,120(17):3045-3052.
[367]Divakaran V, Adrogue J, Ishiyama M, et al. Adaptive and maladptive effects ofSMAD3signaling in the adult heart after hemodynamic pressure overloading[J].Circ Heart Fail.2009,2(6):633-642.
[368]Thum T, Gross C, Fiedler J, et al. MicroRNA-21contributes to myocardial diseaseby stimulating MAP kinase signalling in fibroblasts[J]. Nature.2008,456(7224):980-984.
[369]Liu N, Bezprozvannaya S, Williams AH, et al. MicroRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart[J].Genes Dev.2008,22(23):3242-3254.
[370]Duisters RF, Tijsen AJ, Schroen B, et al. MiR-133and miR-30regulate connectivetissue growth factor:implications for a role of microRNAs in myocardial matrixremodeling[J]. Circ Res.2009,104(2):170-178.
[371]Matkovich SJ, Wang W, Tu Y, et al. MicroRNA-133a protects against myocardialfibrosis and modulates electrical repolarization without affecting hypertrophy inpressure-overloaded adult hearts[J]. Circ Res.2010,106(1):166-175.
[372]Fernandez-Velasco M, Goren N, Benito G, et al. Regional distribution ofhyperpolarization-activated current(If)and hyperpolarization-activated cyclicnucleotide-gated channel mRNA expression in ventricular cells from control andhypertrophied rat hearts[J]. J Physiol.2003,553(2):395-405.
[373]Luo X, Lin H, Pan Z, et al. Downregulation of miRNA-1/miRNA-133contributesto re-expression of pacemaker channel genes HCN2and HCN4in hypertrophicheart. J Biol Chem[J].2008,283:20045-20052.
[374]Zhao Y, Ransom JF, Li A, et al. Dysregulation of cardiogenesis, cardiac conductionand cell cycle in mice lacking miRNA-1-2[J]. Cell.2007,129(2):303-317.
[375]Yang B, Lin H, Xiao J, et al. The muscle-specific microRNA miR-1regulatescardiac arrhythmogenic potential by targeting GJA1and KCNJ2[J]. Nat Med.2007,13(4):486-491.
[376]Terentyev D, Belevych AE, Terentyeva R, et al. MiR-1overexpression enhancesCa(2+)release and promotes cardiac arrhythmogenesis by targeting PP2A regulatorysubunit B56α and causing CaMKII-dependent hyperphosphorylation of RyR2[J].Circ Res.2009,104(4):514-521.
[377]Duan R, Pak C, Jin P. Single nucleotide polymorphism associated with maturemiR-125a alters the processing of pri-miRNA. Hum Mol Genet[J].2007,16(9):1124-1131.
[378]Martin MM, Buckenberger JA, Jiang J, et al. The human angiotensin II type1receptor+1166A/C polymorphism attenuates microRNA-155binding[J]. J BiolChem.2007,282(33):24262-24269.
[379]66. Saunders MA, Liang H, Li WH. Human polymorphism at microRNAs andmicroRNA target sites[J]. Proc Natl Acad Sci USA.2007,104(9):3300-3305.
[380]Mishra PJ, Mishra PJ, Banerjee D, et al. MiRSNPs or MiR-polymorphisms, newplayers in microRNA mediated regulation of the cell:introducing microRNApharmacogenomics[J]. Cell Cycle.2008,7(7):853-858.
[381]Mishra PJ, Bertino JR. MicroRNA polymorphisms:the future of pharmacogenomics,molecular epidemiology and individualized medicine[J]. Pharmacogenomics.2009,10(3):399-416.
[382]da Costa Martins PA, Bourajjaj M, Gladka M, et al. Conditional dicer gene deletionin the postnatal myocardium provokes spontaneous cardiac remodeling[J].Circulation.2008,118(15):1567-1576.
[383]Rao PK, Toyama Y, Chiang HR, et al. Loss of cardiac microRNA-mediatedregulation leads to dilated cardiomyopathy and heart failure[J]. Circ Res.2009,105(6):585-594.
[384]Boyle AJ, Shih H, Hwang J, et al. Cardiomyopathy of aging in the mammalian heartis characterized by myocardial hypertrophy, fibrosis and a predisposition towardscardiomyocyte apoptosis and autophagy[J]. Exp. Gerontol.2011,125(9):467-472.
[385]Watanabe Y, Tomita M, Kanai A. Computational methods for microRNA targetprediction[J]. Methods Enzymol.2007,427:65-86.
[386]Ji R, Cheng Y, Yue J, t al. MicroRNA expression signature and antisense-mediateddepletion reveal an essential role of MicroRNA in vascular neointimal lesionformation[J]. Circ Res.2007,100:1579-1588.
[387]Shan H, Zhang Y, Lu Y, et al. Downregulation of miR-133and miR-590contributesto nicotine-induced atrial remodelling in canines[J]. Cardiovasc Res.2009,83:465-472.
[388]van Rooij E, Sutherland LB, Liu N, et al. A signature pattern of stress-responsivemicroRNAs that can evoke cardiac hypertrophy and heart failure[J]. Proc Natl AcadSci USA.2006,103:18255-18260.
[1] Allessie MA, Boyden PA, Camm AJ, et al. Pathophysiology and prevention of atrialfibrillation[J]. Circulation.2001,103(2):769-777.
[2] Chen LY, Shen W-K. Epidemiology of atrial fibrillation:A current perspective[J].Heart Rhythm.2007,4(1):S1-S6.
[3] Bers DM. Calcium cycling and signaling in cardiac myocytes[J]. Annu Rev Physiol,2008,70(6):23-49.
[4] Nattel S, Burstein B, Dobrev D. Atrial remodeling and atrial fibrillation mechanismsand implications[J]. Circ Arrhythmia Electrophysiol,2008,67(1):62-73.
[5] Nattel S, Maguy A, Le Bouter S, et al. Arrhythmogenic ion-channel remodelling inthe heart:heart failure, myocardial infarction, and atrial fibrillation[J]. Physiol Rev,2007,87(5):425-456.
[6] Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation.A study in awake chronically instrumented goats[J]. Circulation,1995,92(7):1954-1968.
[7] Armouche A, Boknik P, Eschenhagen T, et al. Molecular determinants of altered Ca2+handling in human chronic atrial fibrillation[J]. Circulation,2006,114(3):670-680.
[8] S. Neef, N. Dybkova, S. Sossalla, K. et al. CaMKII-Dependent Diastolic SR Ca2+Leak and Elevated Diastolic Ca2+Levels in Right Atrial Myocardium of PatientsWith Atrial Fibrillation[J]. Circ Res,2010,106(7):1134-1144.
[9] Spach MS, Heidlage JF, Dolber PC, et al. Mechanism of origin of conductiondisturbances in aging human atrial bundles:Experimental and model study[J]. HeartRhythm,2007,36(4):175-185.
[10]Basch RF, Scherer CR, Rub N, et al. Molecular mechanisms of early electricalremodeling;transcriptional down regulation of ion channel subunits reducesI (Ca2+-L)and I(to)in rapid atrial pacing in rabbits[J]. J Am Coll Cardiol,2003,41(4):858-869.
[11]Chou CC, Nihei M, Zhou S, et al. Intracellular calcium dynamics and anisotropicreentry in isolated canine pulmonary veins and left atrium[J]. Circulation,2005,111(5):2889-2897.
[12]Nattel S, Maguy A, Le Bouter S, et al. Arrhythmogenic ion-channel remodelling inthe heart:heart failure, myocardial infarction, and atrial fibrillation[J]. Physiol Rev,2007,87(3):425-456.
[13]Ilse Lenaerts, Virginie Bito, Frank R. Heinzel, et al. Ultrastructural and functionalremodeling of the coupling between Ca2+influx and sarcoplasmic reticulum Ca2+release in right atrial myocytes from experimental persistent atrial fibrillation[J].Circulation Research,2009,105(5):876-878.
[14]Sheehan KA, Blatter LA. Regulation of junctional and non-junctional sarcoplasmicreticulum calcium release in excitation-contraction coupling in cat atrial myocytes[J].J Physiol(Lond),2003,546(2):119-135.
[15]El Armouche A, Boknik P, Eschenhagen T, et al. Molecular determinants of alteredCa2+handling in human chronic atrial fibrillation[J]. Circulation,2006,114(2):670-680.
[16]汤宝鹏,许国军,伊力哈木江·沙比提等.慢性心房颤动患者心房肌钙转运调控蛋白基因转录表达改变的研究[J].中国医学科学院学报,2007,29(5):642-647.
[17]汤宝鹏,许国军,库热西·玉努斯等.心房颤动与心房肌钙激活中性蛋白酶基因转录表达改变关系的研究[J].中华心律失常学杂志,2007,11(5):363-367.
[18]Brundel BJ, Ausma J, van Gelder IC, et al. Activation of proteolysis by calpains andstructural changes in human paroxysmal and persistent atrial fibrillation[J].Cardiovasc Res,2002,54(2):315-324.
[19]Spach MS, Heidlage JF, Dolber PC, et al. Mechanism of origin of conductiondisturbances in aging human atrial bundles:Experimental and model study[J]. HeartRhythm,2007,4(2):175-185.
[20]Evgeny P. Anyukhovsky, Eugene A. Sosunov, Parag Chandra, et al. Age-associatedchanges in electrophysiologic remodeling:a potential contributor to initiation of atrialfibrillation[J]. Cardiovascular Research,2005,66(4):353-363.
[2] ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation[J].Eur Heart J.2001,22:1852-1932.
[3] Tsang TS, Miyasaka Y, Barnes ME, et al. Epidemiological profile of atrialfibrillation:a contemporary perspective[J]. Prog Cardiovasc Dis.2005,48:1-8.
[4] Mazzini MJ, Monahan KM. Pharmacotherapy for atrial arrhythmias:present andfuture[J]. Heart Rhythm.2008,5:S26-31.
[5] Nattel S. New ideas about atrial fibrillation50years on[J]. Nature.2002,415:219-26.
[6] Chen LY, Shen W-K. Epidemiology of atrial fibrillation:A current perspective[J].Heart Rhythm.2007,4:S1-S6.
[7] Allessie MA, Boyden PA, Camm AJ, et al. Pathophysiology and prevention of atrialfibrillation[J]. Circulation.2001;103:769-777.
[8] Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime Risk for Development of AtrialFibrillation The Framingham Heart Study[J]. Circulation,2004;110(3):1042-1046.
[9]中华医学会心血管病分会.中国部分地区心房颤动住院病例回顾性调查[J].中华心血管病杂志.2003,31(4):913-916.
[10] Yue L, Feng J, Gaspo R, et al. Ionic remodeling underlying action potential changesin a canine model of atrial fibrillation[J]. Circ Res.1997,81:512-525.
[11] Brundel B. J. J. M, Van Gelder I. C, Henning R. H, et al. Ion channel remodeling isrelated to intra-operative atrial refractory periods in patients with paroxysmal andpersistent atrial fibrillation[J]. Circulation.2001,103:684-690.
[12] Cha TJ, Ehrlich JR, Zhang L, et al. Dissociation between ionic remodeling andability to sustain atrial fibrillation during recovery from experimental congestiveheart failure[J]. Circulation.2004,109:412-418.
[13] Ausma J, Wijffels M, Thone F, et al. Structural changes of atrial myocardium due tosustained atrial fibrillation in the goat[J]. Circulation.1997,96:3157-3163.
[14] Thijssen V. L. J. L, Ausma J, Liu G. S, et al. Structural changes of atrial myocardiumduring chronic atrial fibrillation[J]. Cardiovasc Pathol.2000,9:17-28.
[15] Courtemanche M, Ramirez R. F, Nattel S. Ionic mechanisms underlying humanatrial action potential properties:insights from a mathematical model[J]. Am JPhysiol.1998,275:H301-H321.
[16] Nattel S. Atrial electrophysiological remodeling caused by rapid atrial activation:underlying mechanisms and clinical relevance to atrial fibrillation[J]. Cardiovasc Res.1999,42:298-308.
[17] Yue L, Melnyk P, Gaspo R, et al. Molecular mechanisms underlying ionicremodeling in a dog model of atrial fibrillation[J]. Circ Res.1999,84:776-784.
[18] Van Wagoner D. R, Pond A. L, McCarthy P. M, et al. Outward K+current densitiesand Kv1.5expression are reduced in chronic human atrial fibrillation[J]. Circ Res.1997,80:1-10.
[19] Van Wagoner D. R, Pond A. L, Lamorgese M, et al. Atrial L-type Ca2+currents andhuman atrial fibrillation[J]. Circ Res.1999,85:428-436.
[20] Gaspo R, Bosch R. F, Bou-Abboud E, et al. Tachycardia-induced changes in Na+current in a chronic dog model of atrial fibrillation[J]. Circ Res.1997,81:1045-1052.
[21] Brundel B. J. J. M, Van Gelder I. C, Henning R. H, et al. Alterations in potassiumchannel gene expression in atria of patients with persistent and paroxysmal atrialfibrillation[J]. J Am Coll Cardiol.2001,37:926-932.
[22] Dobrev D, Graf E, Wettwer E, et al. Molecular basis of downregulation ofG-protein-coupled inward rectifying K+current(IK, ACh)in chronic human atrialfibrilation[J]. Circulation.2001,104:2551-2557.
[23] Coutu P, Chartier D, Nattel S. Comparison of Ca2+handling properties of caninepulmonary vein and left atrial cardiomyocytes[J]. Am J Physiol Heart Circ Physiol.2006,291:H2290-H2300.
[24] El-Armouche A, Boknik P, Eschenhagen T, et al. Molecular determinants of alteredCa2+handling in human chronic atrial fibrillation[J]. Circulation.2006,114:670-680.
[25] Kubalova Z, Gyorke I, Terentyeva R, et al. Modulation of cytosolic and intra-sarcoplasmic reticulum calcium waves by calsequestrin in rat cardiac myocytes[J]. JPhysiol.2004,561:515-524.
[26] Terentyev D, Nori A, Santoro M, et al. Abnormal interactions of calsequestrin withthe ryanodine receptor calcium release channel complex linked to exercise-inducedsudden cardiac death[J]. Circ Res.2006,98:1151-1158.
[27] Wijffels M. C, Kirchhof C. J, Dorland R, et al. Atrial fibrillation begets atrialfibrillation:A study in awake chronically instrumented goats[J]. Circulation.1995,92:1954-1968.
[28] Ausma J, Wijffels M, Thone F, et al. Structural Changes of atrial myocardium due tosustained atrial fibrillation in the goat[J]. Circulation.1997,96:3157-3163.
[29] Daoud EG, Bogun F, Goyal R, et al. Effect of atrial fibrillation on atrialrefractoriness in humans[J]. Circulation.1996,94:1600-1606.
[30] Frustaci A, Chimenti C, Bellocci F, et al. Histological substrate of atrial biopsies inpatients with lone atrial fibrillation[J]. Circulation.1997,96:1180-1184.
[31] Goette A, Honeycutt C, Langberg JJ. Electrical remodeling in atrial fibrillation:Timecourse and mechanisms[J]. Circulation.1996,94:2968-2974.
[32] Ausma J, Dispersyn GD, Duimel H, et al. Changes in ultrastructural calciumdistribution in goat atria during atrial fibrillation[J]. J Mol Cell Cardiol.2000,32:355-364.
[33] Schotten U, Ausma J, Stellbrink C, et al. Cellular mechanisms of depressed atrialcontractility in patients with chronic atrial fibrillation[J]. Circulation.2001,103:691-698.
[34] Jayachandran JV, Zipes DP, Weksler J, et al. Role of the Na+/H+exchanger inshort-term atrial electrophysiological remodeling[J]. Circulation.2000,101:1861-1866.
[35] Gao WD, Atar D, Liu Y, et al. Role of troponin I proteolysis in the pathogenesis ofstunned myocardium[J]. Circ Res.1997,80:393-399.
[36] Gurevitch J, Frolkis I, Yuhas Y, et al. Anti-tumor necrosis factor-alpha improvesmyocardial recovery after ischemia and reperfusion[J]. J Am Coll Cardiol.1997,30:1554-1561.
[37] Ke L, Qi XY, Dijkhuis AJ, et al. Calpain mediates cardiac troponin degradation andcontractile dysfunction in atrial fibrillation[J]. J Mol Cell Cardiol.2008,45:685-693.
[38] Brundel BJ, Ausma J, van Gelder IC, et al. Activation of proteolysis by calpains andstructural changes in human paroxysmal and persistent atrial fibrillation[J].Cardiovasc Res.2002,54(2):380-389.
[39] Hyun DH, Hernandez JO, Mattson MP, et al. The plasma membrane redox system inaging[J]. Ageing Res Rev.2006,5:209-220.
[40] Blasco MA. Telomeres and human disease:ageing, cancer and beyond[J]. Nat RevGenet.2005,6:611-622.
[41] Go AS. The epidemiology of atrial fibrillation in elderly persons:the tip of theiceberg[J]. Am J Geriatr Cardiol.2005,14:56-61.
[42] Anyukhovsky EP, Sosunov EA, Chandra P, et al. Age-associated changes inelectrophysiologic remodeling:a potential contributor to initiation of atrialfibrillation[J]. Cardiovasc Res.2005,66:353-363.
[43] Anyukhovsky EP, Sosunov EA, Plotnikov A, et al. Cellular electrophysiologicproperties of old canine atria provide a substrate for arrhythmogenesis[J].Cardiovasc Res.2002,54:462-469.
[44] Weber KT, Pick R, Jalil JE, et al. Patterns of myocardial fibrosis[J]. J Mol CellCardiol.1989,21(Suppl5):121-131.
[45] Allessie M, Schotten U, Verheule S, et al. Gene therapy for repair of cardiacfibrosis:A long way to Tipperary[J]. Circulation.2005,111:391-393.
[46] Spach MS, Heidlage JF, Barr RC, et al. Cell size and communication:role instructural and electrical development and remodeling of the heart[J]. Heart Rhythm.2004,1:500-515.
[47] Spach MS, Dolber PC. Relating extracellular potentials and their derivatives toanisotropic propagation at a microscopic level in human cardiac muscle:Evidencefor electrical uncoupling of side-to-side fiber connections with increasing age[J].Circ Res.1986,58:356-371.
[48] de Bakker JM, van Rijen HM. Continuous and discontinuous propagation in heartmuscle[J]. J Cardiovasc Electrophysiol.2006,17:567-573.
[49] Narayan SM, Bode F, Karasik PL, et al. Alternans of atrial action potentialsduring atrial flutter as a precursor to atrial fibrillation[J]. Circulation.2002,106:1968-1973.
[50] Spach MS, Heidlage JF, Dolber PC, et al. Mechanism of origin of conductiondisturbances in aging human atrial bundles:experimental and model study[J]. HeartRhythm.2007,4:175-185.
[51] Spach MS, Heidlage JF. The stochastic nature of cardiac propagation at amicroscopic level:Electrical description of myocardial architecture and itsapplication to conduction[J]. Circ Res.1995,76:366-380.
[52] Nygren A, Fiset C, Firek L, et al. Mathematical model of an adult human atrialcell:the role of K+currents in repolarization[J]. Circ Res.1998,82:63-81.
[53] Chen PS, Wolf PD, Dixon EG, et al. Mechanism of ventricular vulnerability tosingle premature stimuli in open-chest dogs[J]. Circ Res.1988,62:1191-1209.
[54] Dobrev D, Ravens U. Remodeling of cardiomyocyte ion channels in human atrialfibrillation[J]. Basic Res Cardiol.2003,98:137-148.
[55] Dhamoon AS, Jalife J. The inward rectifier current(IK1)controls cardiac excitabilityand is involved in arrhythmogenesis[J]. Heart Rhythm.2005,2:316-324.
[56] Jalife J. Rotors and spiral waves in atrial fibrillation[J]. J Cardiovasc Electrophysiol.2003,14:776-780.
[57] Miragoli M, Gaudesius G, Rohr S. Electrotonic modulation of cardiac impulseconduction by myofibroblasts[J]. Circ Res.2006,98:801-810.
[58] Camelliti P, Green CR, LeGrice I, et al. Fibroblast network in rabbit sinoatrialnode:structural and functional identification of homogeneous and heterogeneouscell coupling[J]. Circ Res.2004,94:828-835.
[59] Kamkin A, Kiseleva I, Isenberg G, et al. Cardiac fibroblasts and themechano-electric feedback mechanism in healthy and aged hearts[J]. Prog BiophysMol Biol.2003,82:111-120.
[60] Bartel DP. MicroRNAs, genomics, biogenesis, mechanism and function[J]. Cell.2008,116:281-297.
[61] van Rooij E, Sutherland LB, Qi X, et al. Control of stress-dependent cardiac growthand gene expression by a microRNA[J]. Science.2007,316:575-579.
[62] Zhao Y, Samal E, Srivastava D. Serum response factor regulates a muscle-specificmicroRNA that targets Hand2during cardiogenesis[J]. Nature.2005,436(7048):214-220.
[63] Yang B, Lin H, Xiao J, et al. The muscle-specific microRNA miR-1regulatescardiac arrhythmogenic potential by targeting GJA1and KCNJ2[J]. Nat Med.2007,13(4):486-491.
[64] Zhao Y, Ransom JF, Li A, et al. Dysregulation of cardiogenesis, cardiac conductionand cell cycle in mice lacking miRNA-1[J]. Cell.2007,129(2):303-317.
[65] van Rooij E, Sutherland LB, Liu N, et al. A signature pattern of stress-responsivemicroRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl AcadSci USA.2006;103(48):18255-18260.
[66] Xiao J, Luo X, Lin H, et al. MicroRNA miR-133represses HERG K+channelexpression contributing to QT prolongation in diabetic hearts[J]. J Biol Chem.2007,282(17):12363-12367.
[67] Thum T, Galuppo P, Wolf C, et al. MicroRNAs in the human heart-a clue to fetalgene reprogramming in heart failure[J]. Circulation.2007,116(3):258-267.
[68] Wang GK, Zhu JQ, Zhang JT, et al. Circulating microRNA:a novel potentialbiomarker for early diagnosis of acute myocardial infarction in humans[J]. EurHeart J.2010,31(6):659-666.
[69] Tijsen AJ, Creemers EE, Moerland PD, et al. MiR423-5p as a circulating biomarkerfor heart failure[J]. Circ Res.2010,106(6):1035-1039.
[70] Matkovich SJ, van Booven DJ, Youker KA, et al. Reciprocal regulation ofmyocardial microRNAs and messenger RNA in human cardiomyopathy andreversal of the microRNA signature by biomechanical support[J]. Circulation.2009,119(9):1263-1271.
[71] Schipper ME, van Kuik J, de Jonge N, et al. Changes in regulatory microRNAexpression in myocardium of heart failure patients on left ventricular assist devicesupport[J]. J Heart Lung Transplant.2008,27(12):1282-1285.
[72] Krutzfeldt J, Rajewsky N, Braich R, et al. Silencing of microRNAs in vivo with‘antagomirs’ Nature[J].2005,438(7068):685-689.
[73] van Rooij E, Sutherland LB, Thatcher JE, et al. Dysregulation of microRNAs aftermyocardial infarction reveals a role of miR-29in cardiac fibrosis[J]. Proc Natl AcadSci USA.2008,105:13027-13032.
[74] Care A, Catalucci D, Felicetti F, et al. MicroRNA-133controls cardiachypertrophy[J]. Nat Med.2007,13(5):613-618.
[75] Thum T, Gross C, Fiedler J, et al. MicroRNA-21contributes to myocardial diseaseby stimulating MAP kinase signalling in fibroblasts[J]. Nature.2008,456(7224):980-984.
[76] Lin Z, Murtaza I, Wang K, et al. MiR-23a functions downstream of NFATc3toregulate cardiac hypertrophy[J]. Proc Natl Acad Sci USA.2009,106(29):12103-12108.
[77] Esau C, Davis S, Murray SF, et al. MiR-122regulation of lipid metabolism revealedby in vivo antisense targeting[J]. Cell Metab.2006,3(2):87-98.
[78] Elmen J, Lindow M, Schutz S, et al. LNA-mediated microRNA silencing innon-human primates[J]. Nature.2008,452(7189):896-899.
[79] Suckau L, Fechner H, Chemaly E, et al. Long-term cardiac-targeted RNAinterference for the treatment of heart failure restores cardiac function and reducespathological hypertrophy[J]. Circulation.2009,119(9):1241-1252.
[80] Wen Dun1, Takuya Yagi1, Michael R, et al. Calcium and potassium currents in cellsfrom adult and aged canine right atria[J]. Cardiovascular Research.2003,58:526-534.
[81] Josephson IR, Guia A, Stern MD, et al. Alterations in properties of L-type Ca2+channels in aging heart[J]. J Mol Cell Cardiol.2002,34:297-308.
[82] Sosunov EA, Anyukhovsky EP, Rosen MR. The adrenergic-cholinergic interactionthat modulates repolarization in the atrium is altered with aging[J]. J CardiovascElectrophysiol.2002,13:374-379.
[83] Chou CC, Nihei M, Zhou S, et al. Intracellular calcium dynamics and anisotropicreentry in isolated canine pulmonary veins and left atrium[J]. Circulation.2005,111:2889-2897.
[84] Nattel S, Maguy A, Le Bouter S, et al. Arrhythmogenic ion-channel remodelling inthe heart:heart failure, myocardial infarction, and atrial fibrillation[J]. Physiol Rev.2007,87:425-456.
[85] Van Gelder IC, Brundel BJ, Henning RH, et al. Alterations in gene expression ofproteins involved in the calcium handling in patients with atrial fibrillation[J]. JCardiovasc Electrophysiol.1999,10:552-60.
[86] Brundel BJ, Van Gelder IC, Henning RH, et al. Gene expression of proteinsinfluencing the calcium homeostasis in patients with persistent and paroxysmalatrial fibrillation[J]. Cardiovasc Res.1999,42:443-454.
[87] Vest JA, Wehrens XH, Reiken SR, et al. Defective cardiac ryanodine receptorregulation during atrial fibrillation[J]. Circulation.2005,111:2025-2032.
[88] S. Neef, N. Dybkova, S. Sossalla, K. R, et al. CaMKII-Dependent Diastolic SR Ca2+Leak and Elevated Diastolic Ca2+Levels in Right Atrial Myocardium of PatientsWith Atrial Fibrillation[J]. Circ Res.2010,106:1134-1144.
[89] Bers Dm. Excitation-Contraction Coupling and Cardiac Contractile Force.[J]ZDordrecht, Netherlands, Kluwer Academic Publishers.2001.
[90] ZBers DM, Perez-Reyes E. Ca channels in cardiac myocytes:Structure and functionin ZZCa influx and intracellular ZCa release[J]. Cardiovasc Res.1999,42:339-360.
[91] Bean BP. Classes of calcium channels in vertebrate cells[J]. Annu Rev Physiol.1989,51:367-384.
[92] Bean BP. Two kinds of calcium channels in canine atrial cels. ZDifferences inkinetics, selectivity, and pharmacology[J]. JZ Gen Physio.1985, l86:1-30.
[93] Hirano Y, Fozzard HA, January ZCT. Characteristics of L-and T-type Ca2+currentsin canine cardiac Purkinje cells[J]. Am J Physiol Heart Circ Physiol.1989,256:H1478-H1492.
[94] Hagiwara N, Irisawa H, Kameyama M. Contribution of two types of calciumcurrents to the pacemaker potentials of rabbit sino-atrial node cells[J]. J Physiol.1988,359:233-253.
[95] Mitra R, Morad M. Two types of calcium channels in guinea-pig ventricularmyocytes[J]. Proc Natl Acad Sci U S A.1986,83:5340-5344.
[96] Nuss HB, Houser SR. T-type Ca2+current is expressed in hypertrophied adult felineleft ventricular myocytes[J]. Circ Res.1993,73:777-782.
[97] Yuan W, Bets DM. Ca-dependent facilitation of cardiac Ca current is due toCa-calmodulin-dependent protein kinase[J]. Am J Physiol Heart Circ Physiol.1994,267:H982-H993.
[98] Yuan W, Ginsburg KS, Bers DM. Comparison of sarcolemmal calcium channelcurrent in rabbit and rat ventricular myocytes[J]. J Physiol.1996,493:733-746.
[99] Wetzel GT, Chen F, Klitzner TS. Ca2+channel kinetics in acutely isolated fetal,neonatal, and adult rabbit cardiac myocytes[J]. Circ Res.1993,72:1065-1074.
[100]GaughanJP, Hefner CA, Houser SR. Electrophysiological properties of neonatal ratventricular myocytes with α1-adrenergic-induced hypertrophy[J]. AmJ PhysiolHeart Circ Physio.1998,1275:H577-H590.
[101]Cribbs LL, Martin BL, Schroder EA, et al Identification of the T-type calciumchannel(Cav3.1d)in developing mouse heart[J]. Circ Res.2001,88:403-407.
[102]Martfnez ML, Heredia MP, Delgado C. Expression of T-type Ca2+channels inventricular cells from hypertrophied rat hearts[J]. J Mol Cell Cardiol.1999,31:1617-1625.
[103]Jeong SW, Wurster RD. Calcium channel currents in acutely dissociatedintracardiac neurons from adult rats[J]. J Neurophysiol.1997,77:1769-1778.
[104]Lipsius SL, Hiiser J, Blatter LA. Intracellular Ca release sparks atrial pacemakeractivity[J]. News Physiol Sci.2001,16:101-106.
[105]Ruth P, R6hrkasten A, Biel M, et al. Primary structure of the3subunit of theDHP-sensitive calcium channel from skeletal muscle[J]. Science.1989,245:1115-1118.
[106]Jay SD, Ellis SB, McCue A. F, et al. Primary structure of the7subunit of theDHP-sensitive calcium channel from skeletal muscle[J]. Science1990;248:490-492.
[107]Mikami A, Imoto K, Tanabe T, et al. Primary structure and functional expression ofthe cardiac dihydropyridine-sensifive calcium channel[J]. Nature.1989,340:230-233.
[108]Takimoto K, Li D, Nerbonne JM, Levitan ES. Distribution, splicing andglucocorticoid-induced expression of cardiac voltage-gated Ca2+channelmRNAs[J]. J Mol Cell Cardio.1997,129:3035-3042.
[109]Wyatt CN, Campbell V, Brodbeck J, et al. Voltage-dependent binding and calciumchannel current inhibition by an anti-α1D subunit antibody in rat dorsal rootganglion neurones and guinea-pig myocytes[J]. J Physiol.1997,502:307-319.
[110]Jay SD, Sharp AH, Kahl SD, et al. Structural characterization of thedihydropyridine-sensitive calcium channel a1c-subunit and the associated8peptides[J]. J Biol Chem.1991,266:3287-3293.
[111]Wei XY, Pan S, Lang WH, et al. Molecular determinants of cardiac Ca2+channelpharmacology--Subunit requirement for the high affinity and allosteric regulation ofdihydropyridine binding[J]. J Biol Chem.1995,270:27106-27111.
[112]Bangalore R, Mehrke G, Gingrich K, et al. Influence of L-type Ca channela1c-subunit on ionic and gating current in transiently transfected HEK293cells[J].Am J Physiol Heart Circ Physiol.1996,270:H152i-H1528.
[113]Perez-Reyes E, Castellano A, Kim HS, et al. Cloning and expression of acardiac/brain ubunit of the L-type calcium channel[J]. J Biol Chem.1992,267:1792-1797.
[114]Neely A, Wei X, Olcese R, et al. Potentiation by the13subunit of the ratio of theionic current to the charge movement in the cardiac calcium channel[J]. Science.1993,262:575-578.
[115]Mitterdorfer J, Froschmayr M, Grabner M, et al. Calcium channels:The β-subunitincreases the affinity of dihydropyridine and Ca2+binding sites of the α1-subunit[J].FEBS Lett.1994,352:141-145.
[116]Gao TY, Chien AJ, Hosey MM. Complexes of the α1c and β subunits generate thenecessary signal for membrane targeting of class C L-type calcium channels[J]. JBiol Chem.1999,274:2137-2144.
[117]de Waard M, Pragnell M, Campbell KP. Ca2+channel regulation by a conservedsubunit domain[J]. Neuron.1994,13:495-503.
[118]Pragnell M, de Waard M, Mori Y, et al. Calcium channel a1c-subunit binds to aconserved motif in the I-II cytoplasmic linker of the α1-subunit[J]. Nature.1994,368:67-70.
[119]Perez-Reyes E, Cribbs LL, et al. Molecular characterization of a neuronallow-voltage-activated T-type calcium channel[J]. Nature.1998,391:896-900.
[120]Cribbs LL, Lee JH, Yang J, et al. Cloning and characterization of cdH from humanheart, a member of the T-type Ca2+channel gene family[J]. Circ Res.1998,83:103-109.
[121]Lee JH, Daud AN, Cribbs LL, et al. Cloning and expression of a novel member ofthe low voltage-activated T-type calcium channel family[J]. J Neurosci.1999,19:1912-1921.
[122]McCIeskey EW, Ahners W. The Ca channel in skeletal muscle is a large pore[J].Proc Nad Acad Sci U S A.1985,82:7149-7153.
[123]Ellinor PT, Yang J, Sather WA, et al. Ca2+channel selectivity at a single locus forhigh-affinity Ca2+interactions[J]. Neuron.1995,15:1121-1132.
[124]Chen XH, Bezprozvanny I, Tsien RW. Molecular basis of proton block of L-typeCa2+channels[J]. J Gen Physiol.1996,108:363-374.
[125]Chen XH, Tsien RW. Aspartate substitutions establish the concerted action ofP-region glutamates in repeats I and III in forming the pro-tonation site of L-typeCa2+channels[J]. J Biol Chem.1997,272:30002-30008.
[126]Lee KS, Marban E, Tsien RW. Inactivation of calcium channels in mammalian heartcells:Joint dependence on membrane potential and intracellular calcium[J]. JPhysiol.1985,364:395-411.
[127]Kass RS, Sanguinetti MC. Inactivation of calcium channel current in the calfcardiac Purkinje fiber:Evidence for voltage-and calcium-mediated mechanisms[J]. JGen Physiol.1984,84:705-726.
[128]Hadley RW, Hume JR. An intrinsic potential-dependent inactivation mechanismassociated with calcium channels in guinea-pig myocytes[J]. J Physiol.1987,389:205-222.
[129]Puglisi JL, Yuan W, Bassani JWM, et al. Ca2+influx through Ca2+channels in rabbitventricular myocytes during action potential clamp:Influence of temperature[J].Circ Res.1999,85:7-16.
[130]H6fer GF, Hohenthanner K, Banmgartuer W, et al. Intracellular Ca2+inactivatesL-type Ca2+channels with a Hill coefficient of approximately1and an inhibitionconstant of approximately4gM by reducing channel's open probability[J]. BiophysJ.1997,73:1857-1865.
[131]Zuhlke RD, Reuter I-I. Ca2+sensitive inactivation of L-type Ca2+channels dependson multiple cytoplasmic amino acid sequences of the cqc subunit[J]. Proc Natl AcadSci U S A.1998,95:3287-3294.
[132]Peterson BZ, DeMaria CD, Yue DT. Calmodulin is the Ca2+sensor forCa2+-dependent inactivation of L-type calcium channels[J]. Neuron.1999,22:549-558.
[133]Qin N, Olcese R, Bransby M, et al. Ca2+-induced inhibition of the cardiac CaV1.2channel depends on calmodulin[J]. Proc Nad Acad Sci U S A.1999,96:2435-2438.
[134]Ztihlke RD, Pitt GS, Deisseroth K, et al. Calmodulin supports both inactivation andfacilitation of L-type calcium channels[J]. Nature.1999,399:159-162.
[135]Sipido KR, Callewaert G, Carmeliet E. Inhibition and rapid recovery of Ca2+currentduring Ca2+release from sarcoplasmic reticulum in guinea pig ventricularmyocytes[J]. Circ Res.1995,76:102-109.
[136]January CT, Riddle JM. Early afterdepolarizations:Mechanism of induction andblock. A role for L-type Ca2+current[J]. Circ Res.1989,64:977-990.
[137]Tseng GN. Calcium current restitution in mammalian ventricular myocytes ismodulated by intracellular calcium[J]. Circ Res.1988,63:468-482.
[138]Hryshko LV, Bets DM. Ca2+current fadlitation during post-rest recovery dependson Ca2+entry[J]. Am J Physiol Heart Circ Physiol.1990,259:H951-H961.
[139]Zygmunt AC, Maylie J. Stimulation-dependent facilitation of the high thresholdcalcium current in guinea-pig ventricular myocytes[J]. J Physio.1990,1428:653-67I.
[140]Yuan W, Bers DM. Ca-dependent facilitation of cardiac Ca current is due toCa-calmodulin-dependent protein kinase[J]. Am J Physiol Heart Circ Physiol.1994,267:H982-H993.
[141]Anderson ME, Braun AP, Schulman H, et al. Multifunctonal Ca2+/ealmodulin-ependent protein kinase mediates Ca2+-induced enhancement of the L-type Ca2+current in rabbit ventricular myocytes[J]. Circ Res.1994,75:854-861.
[142]Xiao RP, Cheng H, Lederer WJ, et al. Dual regulation of Ca2+/calmodulin-dependent kinase II activity by membrane vokage and by calcium influx[J]. ProcNad Acad Sci U S A.1994,91:9659-9663.
[143]Dzhnra I, Wu Y, Colbran RJ, et al. Calmodulin kinase determines calcium-dependent facilitation of L-type calcium channels[J]. Nat Cell Biol.2000,2:173-177.
[144]Pietrobon D, Hess P. Modal gating of L-type calcium channels[J]. Biophys J.1990,57:24a.
[145]Sculptoreanu A, Rotman E, Takahashi M, et al. Voltage-dependent potefftiation ofthe activity of cardiac L-type calcium channel al subunits due to phosphorylation bycAMP-dependent protein kinase[J]. Proc Natl Acad Sci U S A.1993,90:10135-10139.
[146]Kamp TJ, Hu H, Marb~n E. Vokage-dependent facilitation of cardiac L-type Cachannels expressed in HEK-293cells requires[J]. Am J Physiol Heart Circ Physiol.2000,278:H126-H136.
[147]Lew WYW, Hryshko LV, Bets DM. Dihydropyridine receptors are primarilyfunctional L-type Ca channels in rabbit cardiac myocytes[J]. Circ Res.1991,69:1139-1145.
[148]Grantham CJ, Cannell MB. Ca2+influx during the cardiac action potential in guineapig ventricular myocytes[J]. Circ Res.1996,79-194-200.
[149]Linz KW, Meyer R. Control of L-type calcium current during the action potential ofguinea-pig ventricular myocytes[J]. J Physiol.1998,513:425--442.
[150]Mikami A, Imoto K, Tanabe T, et al. Primary structure and functional expression ofthe cardiac dihydropyridine-sensitive calcium channel[J]. Nature.1989,340:230-233.
[151]Wakamori M, Mikala G, Schwartz A, et al. Single-channel analysis of a clonedhuman heart L-type Ca2+channel alpha1subunit and the effects of a cardiac betasubunit[J]. Biochem Biophys Res Commun.1993,196:1170-1176.
[152]Yang J, Ellinor PT, Sather WA, et al. Molecular determinants of Ca2+selectivity andion permeation in L-type Ca2+channels[J]. Nature.1993,366:158-161.
[153]Hersel J, Jung S, Mohacsi P, et al. Expression of the L-type calcium channel inhuman heart failure[J]. Basic Res Cardiol.2002,97:I4-10.
[154]Meissner G. Regulation of mammalian ryanodine receptors[J]. Front Biosci.2002,7:2072-2080.
[155]Franzini-Armstrong C, Protasi F. Ryanodine receptors of striated muscles:Acomplex channel capable of multiple interactions[J]. Physiol Rev.1997,77:699-729.
[156]Meissner G. Monovalent ion and calcium ion fluxes in sarcoplasmic reticulum[J].Mol Cell Biochem.1983,55:65-82.
[157]Meissner G. Isolation and characterization of two types of sarcoplasmic reticulumvesicles[J]. Biochim Biophys Acta.1975,389:51-68.
[158]Jones LR, Cala SE. Biochemical evidence for functional heterogeneity of cardiacsarcoplasmic reticulum vesicles[J]. J Biol Chem.1981,256:11809-11818.159]Wier WG, Balke CW. Ca2+release mechanisms, Ca2+sparks, and local control ofexcitation-contraction coupling in normal heart muscle[J]. Circ Res.1999,85:770-776.
[160]Marx SO, Gaburjakova J, Gaburjakova M, et al. Coupled gating between cardiaccalcium release channels(ryanodine receptors)[J]. Circ Res.2001,88:1151-1158.
[161]Gatto C, Hale CC, Xu W, et al. Eosin, a potent inhibitor of the plasma membrane Capump, does not inhibit the cardiac Na-Ca exchanger[J]. Biochemistry.1995,34:965-972.
[162]Choi HS, Eisner DA. The role of sarcolemmal Ca2+-ATPase in the regulation ofresting calcium concentration in rat ventricular myocytes[J]. J Physiol.1999,515:109-118.
[163]Choi HS, Eisner DA. The effects of inhibition of the sarcolemmal Ca2+-ATPase onsystolic calcium fluxes and intracellular calcium concent. ration in rat ventricularmyocytes[J]. Pflugers Arch.1999,437:966-971.
[164]Bers DM. Cardiac excitation-contraction coupling[J]. Nature.2002,415:198-205.
[165]HenaffM, Antoine S, Mercadier JJ, et al. The voltage-independent B-type Ca2+channel modulates apoptosis of cardiac myocytes[J]. FASEB J.2002,16:99-101.
[166]Antoine S, Pinet C, Coulombe A. Are B-type Ca2+channels of cardiac myocytesakin to the passive ion channel in the plasma mem-brane Ca2+pump[J]? J MembrBiol.2001,179:37-50.
[167]Pinet C, Antoine S, Filoteo AG, et al. Reincorporated plasma membraneCa2+-ATPase can mediate B-type Ca2+-channels observed in native membrane ofhuman red blood cells[J]. J Membr Biol.2002,187:185-201.
[168]Philipson KD. Na+-Ca2+exchange:Three new tools[J]. Circ Res.2002,90:118-119.
[169]Carafoli E, Brini M. Calcium pumps:Structural basis for and mechanism of calciumtransmembrane transport[J]. Curr Opin Chem Biol.2000,4:152-161.
[170]Strehler EE, Zacharias DA. Role of alternative splicing in generating isoformdiversity among plasma membrane calcium pumps[J]. Physiol Rev.2001,81:21-50.
[171]Monteith GR, Roufogalis BD. The plasma membrane calcium pumpa physiologicalerspective on its regulation[J]. Cell Calcium.1995,18:459-470.
[172]Penniston JT, Enyedi A. Modulation of the plasma membrane Ca2+pump[J]. JMembr Biol.1998,165:101-109.
[173]Takeshima H, Ikemoto T, Nishi M, et al. Generation and characterization of mutantmice lacking ryanodine receptor type3[J]. J Biol Chem.1996,271:19649-19652.
[174]Takeshima H, Komazaki S, Hirose K, et al. Embryonic lethality and abnormalcardiac myocytes in mice lacking ryanodine receptor type2[J]. EMBOJ.1998,17:3309-3316.
[175]Anderson K, Lai FA, Liu QY, et al. Structural and functional charac terization of thepurified cardiac ryanodine receptor-Ca2+release channel complex[J]. J Biol Chem.1989,264:1329-1335.
[176]Sharma MR, Penczek P, Grassucci R, et al. Cryoelectron microscopy and imageanalysis of the cardiac ryanodine receptor[J]. J Biol Chem.1998,273:18429-18434.
[177]Du GG, Sandhu B, Khanna VK, et al. Topology of the Ca2+release channel ofskeletal muscle sarcoplasmic reticulum(RyR1)[J]. Proc Nad Acad Sci USA.2002,99:16725-6730.
[178]Tinker A, Lindsay AR, Williams AJ. Cation conduction in the calcium releasechannel of the cardiac sarcoplasmic reticulum under physiological and pathophysiological conditions[J]. Cardiovasc Res.1993,27:1820-1825.
[179]Chen DP, Xu L, Tripathy A, et al. Selectivity and permeation in calcium releasechannel of cardiac muscle:Alkali metal ions[J]. Biophys J.1999,76:1346-1366.
[180]MacKrill JJ. Protein-protein interactions in intracellular Ca2+release channelfunction[J]. Biochem J.1999,337:345-361.
[181]Marks AR. Ryanodine receptors, FKBP12, and heart failure[J]. Front Biosci.2002,7:970-977.
[182]Xu L, Meissner G. Regulation of cardiac muscle Ca2+release channel bysarcoplasmic reticulum lumenal Ca2+[J]. Biophys J.1998,75:2302-2312.
[183]Sitsapesan R, Williams AJ. Regulation of current flow through ryanodine receptorsby luminal Ca2+[J]. J Membr Biol.1997,159:179-185.
[184]Nunogaki K, Kasai M. Determination of the rate of rapid pH equilibration acrossisolated sarcoplasmic reticulum membranes[J]. Biochem Biophys Res Comm.1986,140:934-940.
[185]Anderson ME. Calmodulin and the Philosopher's stone:Changing Ca2+intoarrhythmias[J]. J Cardiovasc Electrophysiol.2002,13:195-197.
[186]Balshaw DM, Yamaguchi N, Meissner G. Modulation of intracellular calciumrelease channels by calmodulin[J]. J Membr Biol.2002,185:1-8.
[187]Yamaguchi N, Xin C, Meissner G. IdentifiCation of apocalmodulin and Ca2+calmodulin regulatory domain in skeletal muscle Ca2+release channel, ryanodinereceptor[J]. J Biol Chem.2001,276:22579-22585.
[188]Eu JP, Sun J, Xu L. The skeletal muscle calcium release channel:Coupled02sensorand NO signaling functions[J]. Cell.2000,102:499-509.
[189]Xu L, Eu JP, Meissner G, et al. Activation of the cardiac calcium releasechannel(ryanodine receptor)by poly-S-nitrosylation[J]. Science.1998,279:234-237.
[190]Eu JP, Xu L, Stamler JS, et al. Regulation of ryanodine receptors by reactivenitrogen species[J]. Biochem Pharmacol.1999,57:1079-1084.
[191]Ziolo MT, Katoh H, Bers DM. Positive and negative effects of nitric oxide on Ca2+sparks:Influence of beta adrenergic stimulation[J]. Am J Physiol.2001,281:2295-H2303.
[192]PetroffMG, Kim SH, Pepe S, et al. Endogenous nitric oxide mechanisms mediatethe stretch dependence of Ca2+release in cardiomyocytes[J]. Nature Cell Biol.2001,3:867-873.
[193]Sun J, Xu L, EuJP, et al. Nitric oxide, NOC-12and S-nitrosoglu-tathione modulatethe skeletal muscle calcium release ehannel/ryan-odine receptor by differentmechanisms:An allosteric function for02in S-nitrosylation of the channel[J]. J BiolChem.2003,278:8184-8189.
[194]Marx S, Reiken S, Hisamatsu Y, et al. Phosphorylation-dependent regulation ofryanodine receptors:A novel role for leucine/isoleucine zippers[J]. J Cell Biol.2001,153:699-708.
[195]Marx S, Reiken S, Hisamatsu Y, et al. PKA phosphorylation dissociates FKBP12.6from the calcium release channel(ryanodine receptor):Defective regulation infailing hearts[J]. Cell2000;101:365-376.
[196]Bosch RF, Nattel S. Cellular electrophysiology of atrial fibrillation[J]. CardiovascRes.2002,54:259-69.
[197]Verheule S, Wilson E, Banthia S, et al. Direction-dependent conduction abnormallities in a canine model of atrial fibrillation due to chronic atrial dilatation[J]. Am JPhysiol Heart Circ Physiol.2004,287:H634-44.
[198]Willems R, Holemans P, Ector H, et al. Mind the model:effect of instrumentationon inducibility of atrial fibrillation in a sheep model[J]. J Cardiovasc Electrophysiol.2002,13:62-67.
[199]Nattel S, Khairy P, Schram G. Arrhythmogenic ionic remodelling:adaptiveresponses with maladaptive consequences[J]. Trends Cardiovasc Med.2001,11:295-301.
[200]Baba S, Dun W, Hirose M, et al. Sodium current function in adult and aged canineatrial cells[J]. Am J Physiol Heart Circ Physiol.2006,291:H756-H761.
[201]King LM, Opie LH. Glucose and glycogen utilisation in myocardialischemia-changes in metabolism and consequences for the myocyte[J]. Mol CellBiochem.1998,180:3-26.
[202]O’Rourke B, Ramza BM, Marban E. Oscillations of membrane current andexcitability driven by metabolic oscillations in heart cells[J]. Science.1994,265:62-966.
[203]Depre C, Rider M, Hue L. Mechanisms of control of heart glycolysis[J]. Eur JBiochem.1998,258:277-290.
[204]Cortassa S, Aon MA, Marban E, et al. An integrated model of cardiac mitochondrial energy metabolism and calcium dynamics[J]. Biophys J.2003,84:2734-2755,.
[205]Mihm MJ, Yu F, Carnes CA, et al. Impaired myofibrillar energetics and oxidativeinjury during human atrial fibrillation[J]. Circulation.2001,104:174-180.
[206]Strand MA, Louis CF, Mickelson JR. Phosphorylation of porcine skeletal andcardiac muscle sarcoplasmic reticulum ryanodine receptor[J]. Biochim BiophysActa.1993,1175:319-326.
[207]Witcher DR, Kovacs RJ, Schulman H, et al. Unique phosphoration site on thecardiac ryanodine receptor regulates calcium channel activity[J]. J Biol Chem.1991,266:11144-11152.
[208]Hain J, Onoue H, Mayrleitner M, et al. Phosphorylation modulates the function ofthe calcium release channel of sarcoplasmic reticulum from cardiac muscle[J]. JBiol Chem.1995,270:2074-2081.
[209]Eisner DA, Diaz ME, Li Y, et al. Stability and instability of regulation ofintracellular calcium[J]. Exp Physiol.2005,90:3-12.
[210]Katra RP, Laurita KR. Cellular mechanism of calcium-mediated triggered activityin the heart[J]. Circ Res.2005,96:535-542.
[211]Croall DE, DeMartino GN. Calcium-activated neutral protease (calpain)system:structure, function, and regulation[J]. Physiol Rev.1991,71:813-847.
[212]Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodelingduring atrial fibrillation[J]. Cardiovasc Res.2002,54:230-246.
[213]Bers DM. Calcium cycling and signaling in cardiac myocytes[J]. Annu Rev Physiol.2008,70:23-49.
[214]Sorimachi H, Ishiura S, Suzuki K. Structure and physiological function ofcalpains[J]. Biochem J.1997,328(Pt3):721-732.
[215]Saido TC, Sorimachi H, Suzuki K. Calpain:New perspectives in molecular diversityand physiological-pathological involvement[J]. FASEB J.1994,8:814-822.
[216]Carafoli E, Molinari M. Calpain:A protease in search of a function[J]? BiochemBiophys Res Commun.1998,247:193-203.
[217]Sorimachi H, Suzuki K. The structure of calpain[J]. J Biochem.2001,129:653-664.
[218]Huang Y, Wang KK. The calpain family and human disease[J]. Trends Mol Med.2001,7:355-362
[219]Guroff G. A neutral calcium-activated proteinase from the soluble fraction of ratbrain[J]. J Biol Chem.1964,239:149-155.
[220]Meyer WL, Fischer EH, Krebs EG. Activation of skeletal muscle phosphorylase bkinase by Ca2+[J]. Biochemistry.1964,3:1033-1039.
[221]Busch WA, Stromer MH, Goll DE, et al. Ca2+-specific removal of Z lines fromrabbit skeletal muscle[J]. J Cell Biol.1972,52:367-381.
[222]Takai Y, Yamamoto M, Inoue M, et al. A proenzyme of cyclicnucleotide-independent protein kinase and its activation by calcium-dependentneutral protease from rat liver[J]. Biochem Biophys Res Commun.1977,77:542-550.
[223]Ishiura S, Murofushi H, Suzuki K, et al. Studies of a calcium-activated neutralprotease from chicken skeletal muscle:Purification and characterization[J]. JBiochem.1978,84:225-230.
[224]Suzuk K. Nomenclature of calcium dependent proteinase[J]. Biomed Biochim Acta.1991,50:483-484.
[225]Goll DE, Thompson VF, Li H, et al. The calpain system[J]. Physiol Rev.2003,83:731-801.
[226]Melloni E, Michetti M, Salamino F, et al. Molecular and functional properties of acalpain activator protein specific for mu-isoforms[J]. J Biol Chem.1998,273:12827-12831.
[227]Suzuki K, Hata S, Kawabata Y, et al. Structure, activation, and biology of calpain[J].Diabetes.2004,53(Suppl1):S12-S18.
[228]Croall DE, Demartino GN. Calcium-activated neutral protease (calpain) system:Structure, function, and regulation[J]. Physiol Rev.1991,71:813-847.
[229]Moldoveanu T, Campbell RL, Cuerrier D, et al. Crystal structures of calpain-E64and-leupeptin inhibitor complexes reveal mobile loops gating the active site[J]. JMol Biol.2004,343:1313-1326.
[230]Reverter D, Strobl S, Fernandez-Catalan C, et al. Structural basis for possiblecalcium-induced activation mechanisms of calpains[J]. Biol Chem.2001,382:753-766.
[231]Tompa P, Emori Y, Sorimachi H, et al. Domain III of calpain is a Ca2+-regulatedphospholipid-binding domain[J]. Biochem Biophys Res Commun.2001,280:1333-1339.
[232]Minami Y, Emori Y, Imajoh-Ohmi S, et al. Carboxyl-terminal truncation andsite-directed mutagenesis of the EF hand structure-domain of the small subunit ofrabbit calcium-dependent protease[J]. J Biochem.1988,104:927-933.
[233]Hosfield CM, Elce JS, Davies PL, et al. Crystal structure of calpain reveals thestructural basis for Ca2+-dependent protease activity and a novel mode of enzymeactivation[J]. EMBO J.1999,18:6880-6889.
[234]Lin GD, Chattopadhyay D, Maki M, et al. Crystal structure of calcium bounddomain VI of calpain at1.9A resolution and its role in enzyme assembly,regulation, and inhibitor binding[J]. Nat Struct Biol.1997,4:539-547.
[235]Ozaki T, Tomita H, Tamai M, et al. Characteristics of mitochondrial calpains[J]. JBiochem.2007,142:365-376.
[236]Kar P, Samanta K, Shaikh S, et al. Mitochondrial calpain system:An overview[J].Arch Biochem Biophys.2010,495:1-7.
[237]Moldoveanu T, Hosfield CM, Lim D, et al. A Ca2+switch aligns the active site ofcalpain[J]. Cell2002;108:649-660.
[238]Nakagawa K, Masumoto H, Sorimachi H et al. Dissociation of m-calpain subunitsoccurs after autolysis of the N-terminus of the catalytic subunit, and is not requiredfor activation[J]. J Biochem.2001,130:605-611.
[239]Suzuki K, Sorimachi H, Yoshizawa T et al. Calpain:Novel family members,activation, and physiological function[J]. Biol Chem Hoppe-Seyler.1995,376:523-529.
[240]Chakrabarti AK, Dasgupta S, Gadsden RH Sr et al. Regulation of brain m calpainCa2+sensitivity by mixtures of membrane lipids:Activation at intracellular Ca2+level[J]. J Neurosci Res.1996,44:374-380.
[241]Wendt A, Thompson VF, Goll DE. Interaction of calpastatin with calpain[J]. BiolChem.2004,385:465-472.
[242]Zhang L, Ma B, Wu J, et al. Cloning and characterization of the yak gene coding forcalpastatin and in silico analysis of its putative product[J]. Acta Biochim Pol.2010,57:35-41.
[243]Sorimachi H, Kimura S, Kinbara K, et al. Muscle-specific calpain, p94, responsiblefor limb girdle muscular dystrophy type2A, associates with connectin through IS2,a p94-specific sequence[J]. J Biol Chem.1995,270:31158-31162.
[244]Shiraha H, Glading A, Chou J, et al. Activation of m-calpain(calpain II)byepidermal growth factor is limited by protein kinase A phosphorylation ofm-calpain[J]. Mol Cell Biol.2002,22:2716-2727.
[245]A. M. Cuervo and J. F. Dice, Age-related decline in chaperone-mediatedautophagy[J]. J. Biol. Chem.2000,275:31505-31513.
[246]M. Baudry, R. DuBrin, L. Beasley, M. et al. Lynch, Low levels of calpain activity inChiroptera brain:implications for mechanisms of aging[J]. Neurobiol.1986,7:255-258.
[247]E. M. Blalock, N. M. Porter and P. W. Landfield, Decreased G-protein-mediatedregulation and shift in calcium channel types with age in hippocampal cultures[J]. J.Neurosci.1999,19:8674-8684.
[248]H. Manya, M. Inomata, T. Fujimori, M. et al. Nabeshima and T. Endo, Klothoprotein deficiency leads to overactivation of mu-calpain[J]. J. Biol. Chem.2002,277:5503-5508.
[249]L. L. David, J. W. Wright and T. R. Shearer, Calpain II induced insolubilization oflens beta-crystallin polypeptides may induce cataract[J]. Biochim. Biophys. Acta.1992,1139:210-216.
[250]M. J. Kelley, L. L. David, N. Iwasaki, M. et al. Shearer, Alpha-crystallin chaperoneactivity is reduced by calpain II in vitro and in selenite cataract[J]. J. Biol. Chem.1993,268:18844-18849.
[251]M. Kuro-o, Y. Matsumura, H. Aizawa,, M. et al. Nabeshima, Mutation of the mouseklotho gene leads to a syndrome resembling ageing[J]. Nature.1997,390:45-51.
[252]H. Manya, M. Inomata, T. Fujimori, N. M. et al. Nabeshima and T. Endo, Klothoprotein deficiency leads to overactivation of mu-calpain[J]. J. Biol. Chem.2002,277:5503-5508.
[253]M. Averna, R. De Tullio, F. Salamino, R. M. et al. Age-dependent degradation ofcalpastatin in kidney of hypertensive rats[J]. J. Biol. Chem.2001,276:38426-38432.
[254]Goette A, Arndt M, R cken C, et al. Calpains and cytokines in fibrillating humanatria[J]. Am J Physiol Heart Circ Physiol.2002,283:H264-H272.
[255]Bukowska A, Lendeckel U, Hirte D, et al. Activation of the calcineurin signalingpathway induces atrial hypertrophy during atrial fibrillation[J]. Cell Mol Life Sci.2006,63:333-342.
[256]Qi XY, Yeh YH, Xiao L, et al. Cellular signaling underlying atrial tachycardiaremodeling of L-type calcium current[J]. Circ Res.2008,103:845-854.
[257]Jayachandran JV, Zipes DP, Weksler J, M. et al. Role of the Na+/H+exchanger inshort-term atrial electrophysiological remodeling[J]. Circulation.2000,101:1861-1866.
[258]Chen M, Won DJ, Krajewski S, M. et al. Calpain and mitochondria inischemia/reperfusion injury[J]. J Biol Chem.2002,277:29181-29186.
[259]Everett TH, Li H, Mangrum JM, et al. Electrical, morphological, and ultrastruc turalremodeling and reverse remodeling in a canine model of chronic atrialfibrillation[J]. Circulation.2000,102:1454-1460.
[260]Fatkin D, Kuchar DL, Thorburn CW, M. et al. Transesophageal echocar diographybefore and during direct current cardioversion of atrial fibrillation:Evidence foratrial stunning as a mechanism of thrombembolic complications[J]. J Am CollCardiol.1994,23:307-316.
[261]Sanfilippo AJ, Abascal VM, Sheehan M, M. et al. Atrial enlargement as aconsequence of atrial fibrillation. A prospective echocardiographic study[J].Circulation.1990,82:792-797.
[262]Schotten U, Ausma J, Stellbrink C, et al. Cellular mechanisms of depressed atrialcontractility in patients with chronic atrial fibrillation[J]. Circulation.2001,103:691-698.
[263]Schotten U, Greiser M, Benke D, et al. Atrial fibrillation-induced atrial contractiledysfunction:A tachycardiomyopathy of a different sort[J]. Cardiovasc Res.2002,53:192-201.
[264]Arndt M, Lendeckel U, R cken C, et al. Altered expression of ADAMs infibrillating atria[J]. Circulation.2002,105:720-725.
[265]Li Y, Gong ZH, Sheng L, et al. Anti-apoptotic effects of a calpain inhibitor oncardiomyocytes in a canine rapid atrial fibrillation model[J]. Cardiovasc Drugs Ther.2009,23:361-368.
[266]Gafni J, Cong X, Chen SF, M. et al. Calpain-1cleaves and activates caspase-7[J]. JBiol Chem.2009,284:25441-25449.
[267]Choudhury S, Bae S, Kumar SR, et al. Role of AIF in cardiac apoptosis inhypertrophic cardiomyocytes from Dahl salt-sensitive rats[J]. Cardiovasc Res.2010,85:28-37.
[268]Norberg E, Gogvadze V, Ott M, M. et al. An increase in intracellular Ca2+isrequired for the activation of mitochondrial calpain to release AIF during celldeath[J]. Cell Death Differ.2008,15:1857-1864.
[269]Crompton M. The mitochondrial permeability transition pore and its role in celldeath[J]. Biochem J.1999,341:233-249.
[270]Di Lisa F, Menabò R, Canton M, et al. Opening of the mitochondrial permeabilitytransition pore causes depletion of mitochondrial and cytosolic NAD+and is acausative event in the death of myocytes in postischemic reperfusion of the heart[J].J Biol Chem.2001,276:2571-2575.
[271]Goette A, Bukowska A, Dobrev D, et al. Acute atrial tachyarrhythmia inducesangiotensin II type1receptor-mediated oxidative stress and microvascular flowabnormalities in the ventricles[J]. Eur Heart J.2009,30:1411-1420.
[272]Bukowska ASL, Keilhoff G, Hirte D, et al. Mitochondrial dysfunction and redoxsignaling in atrial tachyarrhythmia[J]. Exp Biol Med(Maywood).2008,233:558-574.
[273]Murata M, Akao M, O’Rourke B, et al. Mitochondrial m-calpain plays a role in therelease of truncated apoptosis-inducing factor from the mitochondria[J]. BiochimBiophys Acta.2009,1793:1848-1859.
[274]Arrington DD, Van Vleet TR, Schnellmann RG. Calpain10:A mitochondrial calpainand its role in calcium-induced mitochondrial dysfunction[J]. Am J Physiol CellPhysiol.2006,291:C1159-C1171.
[275]Kar P, Chakraborti T, Samanta K, et al. mu-Calpain mediated cleavage of theNa+/Ca2+exchanger in isolated mitochondria under A23187induced Ca2+stimulation[J]. Arch Biochem Biophys.2009,482:67-76.
[276]Lockshin RA, Facey CO, Zakeri Z. Cell death in the heart[J]. Cardiol Clin.2001,19:1-11.
[277]Reijonen S, Kukkonen JP, Hyrskyluoto A, et al. Downregulation of NF-kappaBsignaling by mutant huntingtin proteins induces oxidative stress and cell death[J].Cell Mol Life Sci.2010,67:1929-1941.
[278]Eckstein J, Verheule S, de Groot NM, et al. Mechanisms of perpetuation of atrialfibrillation in chronically dilated atria. Prog Biophys Mol Biol.2008;97:435-51.
[279]Verheule S, Sato T, Everett Tt, et al. Increased vulnerability to atrial fibrillation intransgenic mice with selective atrial fibrosis caused by overexpression ofTGF-beta1[J]. Circ Res.2004,94:1458-65.
[280]Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium. Fibrosisand renin-angiotensin-aldosterone system[J]. Circulation.1991,83:1849-65.
[281]Yang SS, Han W, Zhou HY, et al. Effects of spironolactone on electrical andstructural remodeling of atrium in congestive heart failure dogs[J]. Chin MedJ(Engl)2008,121:38-42.
[282]Beltrami CA, Finato N, Rocco M, et al. The cellular basis of dilatedcardiomyopathy in humans[J]. J Mol Cell Cardiol.1995,27:291-305.
[283]Rakusan K, Flanagan MF, Geva T, et al. Morphometry of human coronarycapillaries during normal growth and the effect of age in left ventricularpressure-overload hypertrophy[J]. Circulation.1992,86:38-46.
[284]Sharov VG, Sabbah HN, Shimoyama H, et al. Evidence of cardiocyte apoptosis inmyocardium of dogs with chronic heart failure[J]. Am J Pathol.1996,148:141-149.
[285]Arends MJ, Morris RG, Wyllie AH. Apoptosis:the role of endonuclease[J]. Am JPathol.1990,136:593-608.
[286]Krajewski S, Krajewska M, Shabaik A, et al. Immunohistochemical determinationof in vivo distribution of Bax, a dominant inhibitor of Bcl-2[J]. Am J Pathol.1994,145:1323-1336
[287]Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases:influence on cardiac form and function[J]. Physiol Rev.2007,87:1285-342.
[288]Remes J, van Brakel TJ, Bolotin G, et al. Persistent atrial fibrillation in a goat modelof chronic left atrial overload[J]. J Thorac Cardiovasc Surg.2008,136:1005-11.
[289]Knackstedt C, Gramley F, Schimpf T, et al. Association of echocardiographic atrialsize and atrial fibrosis in a sequential model of congestive heart failure and atrialfibrillation[J]. Cardiovasc Pathol.2008,17:318-24.
[290]Kassiri Z, Khokha R. Myocardial extra-cellular matrix and its regulation bymetalloproteinases and their inhibitors[J]. Thromb Haemost.2005,93:212-9.
[291]Herpel E, Pritsch M, Koch A, et al. Interstitial fibrosis in the heart:differences inextracellular matrix proteins and matrix metalloproteinases in end-stage dilated,ischaemic and valvular cardiomyopathy[J]. Histopathology.2006,48:736-47.
[292]Cardin S, Libby E, Pelletier P, et al. Contrasting gene expression profiles in twocanine models of atrial fibrillation[J]. Circ Res.2007,100:425-33.
[293]Bouzeghrane F, Reinhardt DP, Reudelhuber TL, et al. Enhanced expression offibrillin-1, a constituent of the myocardial extracellular matrix in fibrosis[J]. Am JPhysiol Heart Circ Physiol.2005,289:H982-91.
[294]Lin CS, Lai LP, Lin JL, et al. Increased expression of extracellular matrix proteinsin rapid atrial pacing-induced atrial fibrillation[J]. Heart Rhythm.2007,4:938-49.
[295]Ramirez F, Rifkin DB. Extracellular microfibrils:contextual platforms for TGF betaand BMP signaling[J]. Curr Opin Cell Biol.2009,8:42-47.
[296]Spinale FG. Myocardial matrix remodeling and the matrix metalloproteinases:influence on cardiac form and function[J]. Physiol Rev.2007,87:1285-342.
[297]Mukherjee R, Herron AR, Lowry AS, et al. Selective induction of matrixmetalloproteinases and tissue inhibitor of metalloproteinases in atrial andventricular myocardium in patients with atrial fibrillation[J]. Am J Cardiol.2006,97:532-7.
[298]Moe GW, Laurent G, Doumanovskaia L, et al. Matrix metalloproteinase inhibitionattenuates atrial remodeling and vulnerability to atrial fibrillation in a canine modelof heart failure[J]. J Card Fail.2008,14:768-76.
[299]MacLellan W, Schneider M. Death by design. Programmed cell death incardiovascular biology and disease[J]. Circ Res.1997,81:137-144.
[300]Haunstetter A., Izumo S. Apoptosis:Basic mechanism and implication forcardiovascular disease[J]. Circ Res.1998,82:1111-1129.
[301]Olivetti G, Abbi R, Quaini F, et al. Apoptosis in human failing heart[J]. New Engl JMed.1997,336:1131-1141.
[302]Doggrell S, Brown L. Rat models of hypertension, cardiac hypertrophy andfailure[J]. Cardiovasc Res.1998,39:89-105.
[303]Adams J, Sakata Y, Davis M, et al. Enhanced Gαq signaling:a common pathwaymediates cardiac hypertrophy and apoptotic heart failure[J]. Proc Natl Acad SciUSA.1998,95:10140-10145.
[304]Wang Y, Huang S, Sah V, et al. Cardiac muscle cell hypertrophy and apoptosisinduced by distinct members of the p38mitogen-activated protein kinase family[J].J Biol Chem.1998,273:2161-2168.
[305]Wang Y, Su B, Sah V, et al. Cardiac hypertrophy induced by mitogen-activatedprotein kinase kinase7, a specific activator of c-jun NH2-terminal kinase inventricular muscle cells[J]. J Biol Chem.1998,273:5423-5426.
[306]Srivastava R, Sollott S, Khna L, et al. Bcl-2and Bcl-XLblock thapsigargin-inducednitric oxide generation, c-Jun NH2-terminal kinase activity, and apoptosis. Mol CellBiol[J].1999,19:5659-5674.
[307]Aikawa R, Komuro I, Yamazaki T, et al. Oxidative stress activates extracellularsignal-regulated kinases through Src and Ras in cultured cardiac myocytes ofneonatal rats[J]. J Clin Invest.1997,100:1813-1821.
[308]Krown K, Page M, Nguyen C, et al. Tumor necrosis factor-alpha-induced apoptosisin cardiac myocytes[J]. J Clin Invest.1996,98:2854-2865.
[309]Clerk A, Sugden P. Mitogen-activated protein kinases are activated by oxidativestress and cytokines in neonatal ventricular myocytes[J]. Biochem Soc Trans.1997,25:566S.
[310]Adderley S, Fitzgerald D. Oxidative damage of cardiomyocytes is limited byextracellular-regulated kinases1/2-mediated induction of cyclooxygenase-2[J]. JBiol Chem.1999,274:5038-5046.
[311]Erhardt P, Schremser E, Cooper G. B-Raf inhibits programmed cell deathdownstream of cytochrome c release from mitochondria by activating theMEK/ERK pathway[J]. Mol Cell Biol.1999,19:5308-5315.
[312]Kennedy S, Kandel E, Cross T, et al. Akt/protein kinase B inhibits cell death bypreventing the release of cytochrome c from mitochondria[J]. Mol Cell Biol.1999,19:5800-5810.
[313]Molkentin J, Lu J, Antos C, et al. A calcineurin-dependent transcriptional pathwayfor cardiac hypertrophy[J]. Cell.1998;93:215-228.
[314]Uemura A, Naito Y, Matsubara T, et al. Demonstration of a Ca2+/calmodulindependent protein kinase cascade in the hog heart[J]. Biochem Biophys ResCommun.1998;249:355-360.
[315]Cardone M, Roy N. H. R. S, Stennicke H. R, et al. Regulation of cell death proteasecaspase-9by phosphorylation[J]. Science.1998,282:1318-1321.
[316]Narula J, Pandey P, Arbustini E, et al. Apoptosis in heart failure:release ofcytochrome c from mitochondria and activation of caspase-3in humancardiomyopathy[J]. Proc Natl Acad Sci USA.1999,96:8144-8149.
[317]Saikumar P, Dong Z, Weinberg J, et al. Mechanisms of cell death inhypoxia/reoxygenation injury[J]. Oncogene.1998,17:3341-3349.
[318]Berridge M, Tan A, McCoy K, et al. CD95(Fas/Apo-1)-induced apoptosis results inloss of glucose transporter function[J]. J Immunol.1996,156:4092-4099.
[319]Marton A, Mihalik R, Bratincsak A, et al. Apoptotic cell death induced byinhibitors of energy conservation[J]. Eur J Biochem.1997,250:467-475.
[320]Kirshenbaum L, de Moissac D. The bcl-2gene product prevents programmed celldeath of ventricular myocytes[J]. Circulation.1997,96:1580-1585.
[321]Garland J, Halestrap A. Energy metabolism during apoptosis:Bcl-2promotes cellsurvival in hematopoietic cells induced to apoptose by growth factor withdrawal bystabilizing a form of metabolic arrest[J]. J Biol Chem.1997,272:4680-4688.
[322]Taimor G, Lorenz H, Hofstaetter B, et al. Induction of necrosis but not apoptosisafter anoxia and reoxygenation in isolated adult cardiomyocytes of rat[J].Cardiovasc Res.1999,41:147-156.
[323]Olivetti G, Abbi R, Quaini F, et al. Apoptosis in the failing human heart[J]. N Engl JMed.1997,336(16):1131-41.
[324]Colucci WS. Apoptosis in the heart[J]. N Engl J Med.1996,335:1224-1226.
[325]Benjamin IJ, Jalil JE, Tan LB, et al. Isoproterenol-induced myocardial fibrosis inrelation to myocyte necrosis[J]. Circ Res.1989,65:657-670.
[326]orczyca W, Gong J, Darzynkiewicz Z. Detection of DNA strand breaks inindividual apoptotic cells by the in situ terminal deoxynucleotidyl transferase andnick translation assays[J]. Cancer Res.1993,53:1945-1951.
[327]Oberhammer F, Wilson JW, Dive C, et al. Structural basis of end-stage failure inischemic cardiomyopathy in humans[J]. Circulation.1994,89:151-163.
[329]Tanaka M, Ito H, Adachi S, et al. Hypoxia induces apoptosis with enhancedexpression of Fas antigen messenger RNA in cultured neonatal ratcardiomyocytes[J]. Circ Res.1994,75:426-433.
[330]Buerke M, Murohara T, Skurk C, et al. Cardioprotective effect of insulin-likegrowth factor I in myocardial ischemia followed by reperfusion[J]. Proc Natl AcadSci U S A.1995,92:8031-8035.
[331]James TN, St Martin E, Willis PW III, et al. Apoptosis as a possible cause ofgradual development of complete heart block and fatal arrhythmias associated withabsence of the AV node, sinus node, and internodal pathways[J]. Circulation.1996,93:1424-1438.
[332]Itoh G, Tamura J, Suzuki M, et al. DNA fragmentation of human infarctedmyocardial cells demonstrated by the nick end labeling method and DNA agarosegel electrophoresis[J]. Am J Pathol.1995,146:1325-1331.
[333]Cannon PJ, Weiss MB, Sciacca RR. Myocardial blood flow in coronary arterydisease:studies at rest and during stress with inert gas washout techniques[J]. ProgCardiovasc Dis.1977,20:95-120.
[334]Zha HB, Aime-Sempe C, Sato T, et al. Proapoptotic protein Bax heterodim-izeswith Bcl-2and homodimerizes with Bax via a novel domain(BH3)distinct fromBH1and BH2[J]. J Biol Chem.1996,271:7440-7444.
[335]Disertori M, Latini R, Barlera S, et al. Valsartan for prevention of recurrent atrialfibrillation[J]. N Engl J Med.2009,360:1606-17.
[336]Cardin S, Libby E, Pelletier P, et al. Contrasting gene expression profiles in twocanine models of atrial fibrillation[J]. Circ Res.2007,100:425-33.
[337]Mukherjee R, Herron AR, Lowry AS, et al. Selective induction of matrixmetalloproteinases and tissue inhibitor of metalloproteinases in atrial andventricular myocardium in patients with atrial fibrillation[J]. Am J Cardiol.2006,97:532-7.
[338]Lin CS, Lai LP, Lin JL, et al. Increased expression of extracellular matrix proteinsin rapid atrial pacing-induced atrial fibrillation[J]. Heart Rhythm.2007,4:938-49.
[339]Moe GW, Laurent G, Doumanovskaia L, et al. Matrix metalloproteinase inhibitionattenuates atrial remodeling and vulnerability to atrial fibrillation in a canine modelof heart failure[J]. J Card Fail.2008,14:768-76.
[340]Tanaka K, Zlochiver S, Vikstrom KL, et al. The spatial distribution of fibrosisgoverns fibrillation wave dynamics in the posterior left atrium during heartfailure[J]. Circ Res.2007,101:839-847.
[341]Goodwin G, Taylor C, Taegtmeyer H. Regulation of energy metabolism of the heartduring acute increase in heart work[J]. J Biol Chem.1998,273:29530-29539.
[342]Oltvai ZN, Milliman CL, Korsmeyer SJ. Bcl-2heterodimerizes in vivo with aconserved homolog, bax, that accelerates programed cell death[J]. Cell.1993,74:609-619.
[343]X. M. Yin, Z. N. Oltvai and S. J. Korsmeyer. BH1and BH2domains of bcl-2arerequired for inhibition of apoptosis and heterodimerization with Bax[J]. Nature.1994;369:321-333.
[344]Van Bilsen M, Van der Vusse G, Reneman R. Transcriptional regulation ofmetabolic processes:implications for cardiac metabolism[J]. Pflügers Arch.1998,437:2-14.
[345]Marton A, Mihalik R, Bratincsák A, et al. Apoptotic cell death induced byinhibitors of energy conservation[J]. Eur J Biochem.1997,250:467-475.
[346]Cheng EH, Kirsch DG, Clem RJ, et al. Conversion of Bcl-2to a Bax-like deatheffector by caspases[J]. Science.1997,278:1966-8.
[347]Boehm M, Slack F. A developmental timing microRNA and its target regulate lifespan in C. elegans[J]. Science.2005,310:1954-1957.
[348]Chen LH, Chiou GY, Chen YW, et al. MicroRNA and aging:a novel modulator inregulating the aging network[J]. Ageing Res. Rev.2010,9(Suppl1):S59-S66.
[349]Grillari J, Grillari-Voglauer R. Novel modulators of senescence, aging, andlongevity:small non-coding RNAs enter the stage[J]. Exp. Gerontol.2010,45:302-311.
[350]Ikeda S, Kong SW, Lu J, et al. Altered microRNA expression in human heartdisease[J]. Physiol Genomics.2007,31:367-373.
[351]van Rooij E, Sutherland LB, Liu N, et al. A signature pattern of stress-responsivemicroRNAs that can evoke cardiac hypertrophy and heart failure[J]. Proc Natl AcadSci USA.2006,103(48):18255-18260.
[352]Sayed D, Hong C, Chen IY, et al. MicroRNAs play an essential role in thedevelopment of cardiac hypertrophy[J]. Circ Res.2007,100(3):416-424.
[353]Cheng YH, Ji RR, Yue JM, et al. MicroRNAs are aberrantly expressed inhypertrophic heart-do they play a role in cardiac hypertrophy[J]? Am J Pathol.2007;170(6):1831-1840.
[354]Tatsuguchi M, Seok HY, Callis TE, et al. Expression of microRNAs is dynamicallyregulated during cardiomyocyte hypertrophy[J]. J Mol Cell Cardiol.2007,42(6):1137-1141.
[355]van Rooij E, Sutherland LB, Thatcher JE, et al. Dysregulation of microRNAs aftermyocardial infarction reveals a role of miR-29in cardiac fibrosis[J]. Proc Natl AcadSci USA.2008,105:13027-13032.
[356]Roy S, Khanna S, Hussain SR, et al. MicroRNA expression in response to murinemyocardial infarction:miR-21regulates fibroblast metalloprotease-2viaphosphatase and tensin homologue[J]. Cardiovasc Res.2009,82(1):21-29.
[357]Care A, Catalucci D, Felicetti F, et al. MicroRNA-133controls cardiachypertrophy[J]. Nat Med.2007,13(5):613-618.
[358]Matkovich SJ, van Booven DJ, Youker KA, et al. Reciprocal regulation ofmyocardial microRNAs and messenger RNA in human cardiomyopathy andreversal of the microRNA signature by biomechanical support[J]. Circulation.2009,119(9):1263-1271.
[359]Naga Prasad SV, Duan ZH, Gupta MK, et al. A unique microRNA profile inend-stage heart failure indicates alterations in specific cardiovascular signalingnetworks[J]. J Biol Chem.2009,284:27487-27499.
[360]Sucharov C, Bristow MR, Port JD. miRNA expression in the failing humanheart:functional correlates[J]. J Mol Cell Cardiol.2008,45(2):185-192.
[361]Ikeda S, Kong SW, Lu J, et al. Altered microRNA expression in human heartdisease[J]. Physiol Genomics.2007,31(3):367-373.
[362]Thum T, Galuppo P, Wolf C, et al. MicroRNAs in the human heart-a clue to fetalgene reprogramming in heart failure[J]. Circulation.2007,116(3):258-267.
[363]Morin RD, O’Connor MD, Griffith M, et al. Application of massively parallelsequencing to microRNA profiling and discovery in human embryonic stem cells[J].Genome Res.2008,18(4):610-621.
[364]Willenbrock H, Salomon J, Sokilde R, et al. Quantitative miRNA expressionanalysis:comparing microarrays with next-generation sequencing[J]. RNA.2009,15(11):2028-2034.
[365]Cheng Y, Liu X, Zhang S, et al. MicroRNA-21protects against the H2O2-inducedinjury on cardiac myocytes via its target gene PDCD4[J]. J Mol Cell Cardiol.2009,47(1):5-14.
[366]Xu C, Lu Y, Pan Z, et al. The muscle-specific microRNAs miR-1and miR-133produce opposing effects on apoptosis by targeting HSP60, HSP70and caspase-9incardiomyocytes[J]. J Cell Sci.2007,120(17):3045-3052.
[367]Divakaran V, Adrogue J, Ishiyama M, et al. Adaptive and maladptive effects ofSMAD3signaling in the adult heart after hemodynamic pressure overloading[J].Circ Heart Fail.2009,2(6):633-642.
[368]Thum T, Gross C, Fiedler J, et al. MicroRNA-21contributes to myocardial diseaseby stimulating MAP kinase signalling in fibroblasts[J]. Nature.2008,456(7224):980-984.
[369]Liu N, Bezprozvannaya S, Williams AH, et al. MicroRNA-133a regulates cardiomyocyte proliferation and suppresses smooth muscle gene expression in the heart[J].Genes Dev.2008,22(23):3242-3254.
[370]Duisters RF, Tijsen AJ, Schroen B, et al. MiR-133and miR-30regulate connectivetissue growth factor:implications for a role of microRNAs in myocardial matrixremodeling[J]. Circ Res.2009,104(2):170-178.
[371]Matkovich SJ, Wang W, Tu Y, et al. MicroRNA-133a protects against myocardialfibrosis and modulates electrical repolarization without affecting hypertrophy inpressure-overloaded adult hearts[J]. Circ Res.2010,106(1):166-175.
[372]Fernandez-Velasco M, Goren N, Benito G, et al. Regional distribution ofhyperpolarization-activated current(If)and hyperpolarization-activated cyclicnucleotide-gated channel mRNA expression in ventricular cells from control andhypertrophied rat hearts[J]. J Physiol.2003,553(2):395-405.
[373]Luo X, Lin H, Pan Z, et al. Downregulation of miRNA-1/miRNA-133contributesto re-expression of pacemaker channel genes HCN2and HCN4in hypertrophicheart. J Biol Chem[J].2008,283:20045-20052.
[374]Zhao Y, Ransom JF, Li A, et al. Dysregulation of cardiogenesis, cardiac conductionand cell cycle in mice lacking miRNA-1-2[J]. Cell.2007,129(2):303-317.
[375]Yang B, Lin H, Xiao J, et al. The muscle-specific microRNA miR-1regulatescardiac arrhythmogenic potential by targeting GJA1and KCNJ2[J]. Nat Med.2007,13(4):486-491.
[376]Terentyev D, Belevych AE, Terentyeva R, et al. MiR-1overexpression enhancesCa(2+)release and promotes cardiac arrhythmogenesis by targeting PP2A regulatorysubunit B56α and causing CaMKII-dependent hyperphosphorylation of RyR2[J].Circ Res.2009,104(4):514-521.
[377]Duan R, Pak C, Jin P. Single nucleotide polymorphism associated with maturemiR-125a alters the processing of pri-miRNA. Hum Mol Genet[J].2007,16(9):1124-1131.
[378]Martin MM, Buckenberger JA, Jiang J, et al. The human angiotensin II type1receptor+1166A/C polymorphism attenuates microRNA-155binding[J]. J BiolChem.2007,282(33):24262-24269.
[379]66. Saunders MA, Liang H, Li WH. Human polymorphism at microRNAs andmicroRNA target sites[J]. Proc Natl Acad Sci USA.2007,104(9):3300-3305.
[380]Mishra PJ, Mishra PJ, Banerjee D, et al. MiRSNPs or MiR-polymorphisms, newplayers in microRNA mediated regulation of the cell:introducing microRNApharmacogenomics[J]. Cell Cycle.2008,7(7):853-858.
[381]Mishra PJ, Bertino JR. MicroRNA polymorphisms:the future of pharmacogenomics,molecular epidemiology and individualized medicine[J]. Pharmacogenomics.2009,10(3):399-416.
[382]da Costa Martins PA, Bourajjaj M, Gladka M, et al. Conditional dicer gene deletionin the postnatal myocardium provokes spontaneous cardiac remodeling[J].Circulation.2008,118(15):1567-1576.
[383]Rao PK, Toyama Y, Chiang HR, et al. Loss of cardiac microRNA-mediatedregulation leads to dilated cardiomyopathy and heart failure[J]. Circ Res.2009,105(6):585-594.
[384]Boyle AJ, Shih H, Hwang J, et al. Cardiomyopathy of aging in the mammalian heartis characterized by myocardial hypertrophy, fibrosis and a predisposition towardscardiomyocyte apoptosis and autophagy[J]. Exp. Gerontol.2011,125(9):467-472.
[385]Watanabe Y, Tomita M, Kanai A. Computational methods for microRNA targetprediction[J]. Methods Enzymol.2007,427:65-86.
[386]Ji R, Cheng Y, Yue J, t al. MicroRNA expression signature and antisense-mediateddepletion reveal an essential role of MicroRNA in vascular neointimal lesionformation[J]. Circ Res.2007,100:1579-1588.
[387]Shan H, Zhang Y, Lu Y, et al. Downregulation of miR-133and miR-590contributesto nicotine-induced atrial remodelling in canines[J]. Cardiovasc Res.2009,83:465-472.
[388]van Rooij E, Sutherland LB, Liu N, et al. A signature pattern of stress-responsivemicroRNAs that can evoke cardiac hypertrophy and heart failure[J]. Proc Natl AcadSci USA.2006,103:18255-18260.
[1] Allessie MA, Boyden PA, Camm AJ, et al. Pathophysiology and prevention of atrialfibrillation[J]. Circulation.2001,103(2):769-777.
[2] Chen LY, Shen W-K. Epidemiology of atrial fibrillation:A current perspective[J].Heart Rhythm.2007,4(1):S1-S6.
[3] Bers DM. Calcium cycling and signaling in cardiac myocytes[J]. Annu Rev Physiol,2008,70(6):23-49.
[4] Nattel S, Burstein B, Dobrev D. Atrial remodeling and atrial fibrillation mechanismsand implications[J]. Circ Arrhythmia Electrophysiol,2008,67(1):62-73.
[5] Nattel S, Maguy A, Le Bouter S, et al. Arrhythmogenic ion-channel remodelling inthe heart:heart failure, myocardial infarction, and atrial fibrillation[J]. Physiol Rev,2007,87(5):425-456.
[6] Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation.A study in awake chronically instrumented goats[J]. Circulation,1995,92(7):1954-1968.
[7] Armouche A, Boknik P, Eschenhagen T, et al. Molecular determinants of altered Ca2+handling in human chronic atrial fibrillation[J]. Circulation,2006,114(3):670-680.
[8] S. Neef, N. Dybkova, S. Sossalla, K. et al. CaMKII-Dependent Diastolic SR Ca2+Leak and Elevated Diastolic Ca2+Levels in Right Atrial Myocardium of PatientsWith Atrial Fibrillation[J]. Circ Res,2010,106(7):1134-1144.
[9] Spach MS, Heidlage JF, Dolber PC, et al. Mechanism of origin of conductiondisturbances in aging human atrial bundles:Experimental and model study[J]. HeartRhythm,2007,36(4):175-185.
[10]Basch RF, Scherer CR, Rub N, et al. Molecular mechanisms of early electricalremodeling;transcriptional down regulation of ion channel subunits reducesI (Ca2+-L)and I(to)in rapid atrial pacing in rabbits[J]. J Am Coll Cardiol,2003,41(4):858-869.
[11]Chou CC, Nihei M, Zhou S, et al. Intracellular calcium dynamics and anisotropicreentry in isolated canine pulmonary veins and left atrium[J]. Circulation,2005,111(5):2889-2897.
[12]Nattel S, Maguy A, Le Bouter S, et al. Arrhythmogenic ion-channel remodelling inthe heart:heart failure, myocardial infarction, and atrial fibrillation[J]. Physiol Rev,2007,87(3):425-456.
[13]Ilse Lenaerts, Virginie Bito, Frank R. Heinzel, et al. Ultrastructural and functionalremodeling of the coupling between Ca2+influx and sarcoplasmic reticulum Ca2+release in right atrial myocytes from experimental persistent atrial fibrillation[J].Circulation Research,2009,105(5):876-878.
[14]Sheehan KA, Blatter LA. Regulation of junctional and non-junctional sarcoplasmicreticulum calcium release in excitation-contraction coupling in cat atrial myocytes[J].J Physiol(Lond),2003,546(2):119-135.
[15]El Armouche A, Boknik P, Eschenhagen T, et al. Molecular determinants of alteredCa2+handling in human chronic atrial fibrillation[J]. Circulation,2006,114(2):670-680.
[16]汤宝鹏,许国军,伊力哈木江·沙比提等.慢性心房颤动患者心房肌钙转运调控蛋白基因转录表达改变的研究[J].中国医学科学院学报,2007,29(5):642-647.
[17]汤宝鹏,许国军,库热西·玉努斯等.心房颤动与心房肌钙激活中性蛋白酶基因转录表达改变关系的研究[J].中华心律失常学杂志,2007,11(5):363-367.
[18]Brundel BJ, Ausma J, van Gelder IC, et al. Activation of proteolysis by calpains andstructural changes in human paroxysmal and persistent atrial fibrillation[J].Cardiovasc Res,2002,54(2):315-324.
[19]Spach MS, Heidlage JF, Dolber PC, et al. Mechanism of origin of conductiondisturbances in aging human atrial bundles:Experimental and model study[J]. HeartRhythm,2007,4(2):175-185.
[20]Evgeny P. Anyukhovsky, Eugene A. Sosunov, Parag Chandra, et al. Age-associatedchanges in electrophysiologic remodeling:a potential contributor to initiation of atrialfibrillation[J]. Cardiovascular Research,2005,66(4):353-363.