摘要
目的:探讨瑞舒伐他汀对大鼠急性心肌梗死后心功能、心室重构和肌球蛋白重链、基质金属蛋白酶2、金属蛋白酶组织抑制因子2表达的影响。
方法:取60只SD大鼠,随机分为假手术(不结扎冠状动脉)组(S组n=10)和急性心肌梗死(结扎左冠状动脉前降支)组(n=50)。将急性心肌梗死模型制模成功24h后存活的36只大鼠再随机分成瑞舒伐他汀(灌胃瑞舒伐他汀lOmg/kg·d)组(R组n=18)和心肌梗死对照组(M组n=18)。假手术组和心肌梗死对照组每日给以等量生理盐水灌胃。8周后各组存活大鼠行血生化检查、超声心动图及血流动力学测定。处死大鼠,取出心脏测定左室重量指数(LVWI)、左室长轴径(LVLA)、心肌细胞横截面积(CSA),苦味酸-天狼猩红染色测定非梗死区Ⅰ型、Ⅲ型心肌胶原含量,TUNEL法检测非梗死区心肌细胞凋亡指数,应用反转录-聚合酶链反应法检测非梗死区基质金属蛋白酶2(MMP-2)、金属蛋白酶组织抑制因子2(TIMP-2)及心肌肌球蛋白重链(MHC)的表达,免疫组化分析基质金属蛋白酶2(MMP-2)、金属蛋白酶组织抑制因子2 (TIMP-2)在非梗死区的蛋白表达。
结果:
1.各组间血脂、天门冬氨酸转氨酶(AST)、肌酐(Cr)、肌酸激酶(CK)水平差异无统计学意义(P>0.05)。
2.与假手术组相比,心梗对照组及治疗组LVAWT变薄(0.11±0.03mm、0.13±0.02mm vs 0.18±0.02mm,P<0.05),LVPWT变厚(0.24±0.03mm、0.22±0.02mmvs 0.18±0.02mm,P<0.05),左室舒张末内径(LVEDD)增高(0.61±0.06mm、0.51±0.06mm vs 0.39±0.06mm,P<0.05)、短轴缩短率(LVFS)和射血分数(LVEF)降低(0.23±0.05、0.39±0.06 vs 0.58±0.06,P<0.05;0.34±0.06、0.45±0.05 vs 0.71±0.06,P<0.05);与心梗对照组比较,治疗组LVAWT变厚(0.13±0.02mm vs 0.11±0.03mm,P>0.05),LVPWT变薄(0.22±0.02mm vs 0.24±0.03mm,P>0.05),左室舒张末内径(LVEDD)降低(0.51±0.06mm vs 0.61±0.06mm,P<0.05)、短轴缩短率(LVFS)和射血分数(LVEF)增高(0.39±0.06vs 0.23±0.05,P<0.05;0.45±0.05 vs 0.34±0.06,P<0.05)。
3.与假手术组相比,心梗对照组及治疗组术后8周左室收缩压(LVSP)、左室内压最大上升下降速率(±dp/dtmax)显著减低(70±6mmHg.109±11mmHg vs 149±13mmHg,P<0.01;2959±252mmHg/s.4050±193mmHg/s vs 6162±199mHg/s,P<0.01;3159±190mmHg/s.3991±199mmHg/s vs 5153±209mmHg/s,P<0.01),左室舒张末压(LVEDP)显著增高(26±5mmHg、13±3mmHg vs 3±1mmHg,P<0.01);与心梗对照比较,治疗组左室收缩压(LVSP).左室内压最大上升下降速率(±dp/dtmax)明显升高(10g±11mHg vs 70±6mmHg,P<0.01;4050±193mmHg/s vs 2959±252mmHg/s,P<0.01;3991±199mmHg/s vs 3159±190mmHg/s,P<0.01),同时左室舒张末压(LVEDP)回落(13±3mmHg vs 26±53mmHg,P<0.01).
4.与假手术组相比,心梗对照组及治疗组术后8周LVLA.LVWI、CSA显著增高(17.0±0.60mm vs 10.0±0.50mm,P<0.01、14.0±0.51mmvs 10.0±0.50mm, P<0.05;3.60±0.16mg/g vs 2.51±0.21mg/g,P<0.01;2.90±0.19mg/g vs2.51±0.21mg/g,P<0.05;718.55±87.26μm2、515.47±71.57μm2 vs 416.29±63.41μm2,P<0.01);与心梗对照组比较,治疗组LVLA.LVWI.CSA降低(14.0±0.51mm vs 17.0±0.60mm,P<0.05;2.90±0.19mg/g vs 3.60±0.16mg/g,P<0.05;515.47±71.57μm2vs 718.55±87.26μm2,P<0.01)。
5.与假手术组相比,心梗对照组及治疗组非梗死区Ⅰ型、Ⅲ型胶原CVF、心肌细胞凋亡指数明显增高(16.45±1.32、8.79±1.06 vs 5.15±0.62,P<0.01;6.75±0.98、4.31±0.87 vs 2.16±0.55,P<0.01);与心梗对照组比较,治疗组非梗死区工型、Ⅲ型胶原CVF、心肌细胞凋亡指数明显降低(8.79±1.06 vs16.45±1.32,P<0.01;4.31±0.87 vs 6.75±0.98,P<0.01)。
6.与假手术组相比,心梗对照组及治疗组非梗死区α-MHCmRNA表达减少,β-MHCmRNA表达增加(0.23±0.09、0.41±0.10 vs 0.61±0.12,P<0.01;2.23±0.14、1.35±0.09 vs 0.91±0.09,P<0.01);与心梗对照组相比,治疗组非梗死区α-MHCmRNA表达增加,β-MHCmRNA表达减少(0.41±0.10 vs 0.23±0.09.P<0.05;1.35±0.09 vs 2.23±0.14,P<0.05)。
7.与假手术组相比,心梗对照组及治疗组非梗死区MMP-2、TIMP-2表达显著增加(0.45±0.0.07、0.32±0.06 vs 0.14±0.05,P<0.01;0.44±0.08、0.53±0.10 vs 0.20±0.04,P<0.01);与心梗对照组相比,治疗组非梗死区MMP-2表达及MMP-2/TIMP-2比值降低,TIMP-2表达增加(0.32±0.06 vs0.45±0.07,P<0.05;0.81±0.07 vs 1.03±0.10,P<0.01;0.53±0.10 vs 0.44±0.08,P<0.05)。
结论:
1.瑞舒伐他汀具有改善急性心肌梗死后心室重塑、血流动力学和心功能的作用。
2.瑞舒伐他汀能够逆转心肌肌球蛋白重链基因表型改变,减轻非梗死区心肌间质胶原重构,有效防止非梗死区心肌细胞的凋亡。
3.瑞舒伐他汀下调MMP-2表达和MMP-2/TIMP-2比值,上调TIMP-2表达可能是其逆转心脏重构和改善心功能的机制之一。
Objective:To investigate the effects of Rosuvastatin on heart function, ventricular remodeling, myosin heavy chain (MHC), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-2 (TIMP-2) in the rats of acute myocardial infarction.
Methods:Sixty Sprague-Dawley rats were randomly divided into sham operation (no coronary ligation) rats (S group, n=10) and acute myocardial infarction (AMI) rats (n=50) received a ligation of left anterior descending coronary artery.24 hours after successful modelling,36 survived rats were randomly divided into Rosuvastatin gavage group (R group, n=18) and AMI control group (M group, n=18). The rats in Rosuvastatin administration group received a gastric gavage of Rosuvastatin at 10mg/kg/d for eight weeks. The rats in AMI control group and sham operation group were give a gastric gavage of normal saline at the same dosage. Following 8-week administration, the surviving rats in each group were examined by echocardiography, hemodynamics and blood biochemical inspection. All rats were subsequently sacrificed and their hearts were taken out to detect left ventricular weight index (LVWI), left ventricular long axis (LVLA) and cross sectional area of myocardial cells(CSA). Picric acid-Sirius red staining was used to detect type I and type III collagen volume fraction (CVF) in non-infarction zone (NIZ). The index of cardiomyocyte apoptosis in NIZ was tested by TNUEL staining. The expression of MHC, MMP-2 and TIMP-2 mRNA, as well as MMP-2 and TIMP-2 protein in NIZ, were respectively measured by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry staining.
Result:
(1) There was no significant difference of serum lipid, aspartate aminotransferase (AST), creatinine (Cr) and creatine kinase (CK) among different groups.
(2) Compared with group S, the groups of M and R showed a significantly increased left ventricular end diastolic diameter (LVEDD), but a significantly decreased left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF) (all P<0.05). Compared with group M, group R had a significantly decreased LVEDD, but significantly increased LVFS and LVEF(all P<0.05). (3) Compared with group S, the groups of M and R exhibited significantly decreased left ventricular systolic pressure (LVSP) and the maximum change rate of left ventricular pressure rise and fall (±dp/dtmax), but a significantly increased left ventricular end diastolic pressure (LVEDP) (all P<0.01). Compared with group M, group R showed significantly increased LVSP and±dp/dtmax, but a significantly decreased LVEDP(all P<0.01).
(4) Compared with that in group S, LVWI (P<0.05), LVLA (P<0.05) and CSA (P <0.01) significantly increased in group M and group R. Compared with that in group M, the indexes of LVWI (P< 0.05), LVLA(P< 0.05) and CSA (P< 0.01) significantly decreased in group R.
(5) Compared with that in group S, type I CVF, typeⅢCVF and the index of cardiomyocyte apoptosis in NIZ increased significantly in both groups of M and R(all P<0.01). Compared with that in group M, all these three indexes list above decreased significantly in group R(all P<0.01).
(6) Compared with that in group S, a-MHC mRNA expression significantly decreased, butβ-MHC mRNA expression significantly increased in NIZ in both groups of M and R(all P<0.01). Compared that in group M, mRNA expression of a-MHC was significantly higher butβ-MHC was significantly lower in group R(all P<0.05).
(7) Compared with that in group S, mRNA and protein expression of MMP-2 and TIMP-2 in NIZ significantly increased in both groups of M and R(all P<0.01). Compared with that in group M, mRNA and protein expression of MMP-2 and the expression ratio of MMP-2/TIMP-2 significantly decreased, but TIMP-2 expression significantly increased in group R(all P<0.05).
Conclusion:Rosuvatatin effectively improves cardiac remodeling, hemodynamics and heart function following acute myocardial infarction. It is able to reverse the phenotype change of MHC, to attenuate myocardial interstitial collagen remodeling, and to reduce cardiomyocyte apoptosis in non-infarction zone of the left ventricle. However, the improvement effects of Rosuvatatin on ventricular remodeling and heart function may be independent of its lipid-lowering function, but may be associated with its down-regulation of MMP-2 and MMP-2/TIMP-2 ratios, as well as its up-regulation of TIMP-2 expression.
引文
[1]中华医学会心血管病学分会中华心血管病杂志编委会.慢性收缩性心力衰竭治疗建议.中华心血管病杂志2002,30:7-23.
[2]Mann DL. Mechanisms and models in heart failure. Circulation,1999,100(9): 999-1008.
[3]Jugdutt BI.Ventrictdar remodeling after infarction and the extracellular collagen matrix When is enough[J]. Cireulation,2003,108(11):1395-1403.
[4]Jugdutt BI. Remodeling of the myocardium and potential targets in the eoHagen degradation and synthesis pathways[J].Curt Drug Targets Cardiovasc Haematol Disord,2003,3(1):1-30.
[5]CHANCEY A L, BROWER G L, PETERSON J L, et al. Effects of matrix metallopmteinase inhibition on ventricular remodeling due to volume overload[J]. Circulation,2002,105(16):1983-1988.
[6]SIWIK D A, COLUCCI W S. Regulation of matrix metallopmteinases by cytokines and reactive oxygen/nitrogen species in the myocardium[J]. Heart Fail Rew,2004,9(1):43.
[7]Kim HE, Dalai SS, Young E, et al. Disruption of the myocardial extracellular matrix leads to cardiac dysfunction. J Clin Invest,2000,106:857-866.
[8]Bauersaehs J, Galuppo P, Fraeearollo D et al. Improvement of left ventrieular remodeling and function by hydroxymet hylglutaryl coerzyme a reduetase inhibition with cerivastatin in rats with heart failure after myocardial infarction. Circulation,2001,104(9):982-985.
[9]Hayashidani S, Tsutsui H, Shiomi T et aL. Fluvastatin, a 3-hy2droxy-3-met hylglutaryl eoenzyme a reduetase inhibitor, attenuates left ventfieular remodeling and failure after experimental myocardial infarction. Circulation,2002,105(7): 868-873.
[10]Bergmana MW,Rechner C, Freund C, et al Statins inhibit reoxygenation induced cardiomyocyte apotosis role for glycogen sythase kinase 3βand transcription factor β catenin [J] J Mol Cell Cardiol,2004, 37:681-690.
[11]McTaggart F, Buckett L, Davidson R,Holdgate G, McCormick A, Schneck D, Smith G, Warwick M. Preclinical and clinical pharmacology of Rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001,87:28B-32B.
[12]Florkowski CM,Molyneux SL,George PM,et al.Rosuvastatin in older patients with systolic heart failure[J].N Engl J Med,2008,358(12):1301-8.
[13]Gissi-HF Investigators,Tavazzi L,MaggioniAP,et al.Effect ofrosuvastatin in patients with chronic heart failure (the GISSI-HF trial):a randomised,doble-blind,placebo-controlled trial [J]. Lancet,2008,372(9645): 1231-9.
[14]Kim YS,Ahn Y,Hong MH,et al.Rosuvastatin suppresses the inflammatory responses through inhibition of c-Jun N-terminal kinaseand nuclear factor-kappa B in endothelial cells[J].J cardiovasc Pharmarol,2007,49(6):376-383.
[15]Sam F,Sawyer DB, Chang DL, et al. Progressive left ventricular remodeling and apoptosis late after myocardial infarction on mouse heart[J]. Am J Physiol Heart Cirl Physiol,2000,279(1):H422-H428.
[16]Agata J,Chao J. Kallikmin gone delivery improves cardiac reserve and attenuates remodeling after myocardial infarction[J]. Hypertension,2002,40(5):653-659.
[17]Izumiya Y,Kim S,Izumi Y,et al. Apoptosis singnal-regulating kinase 1 plays a pivotal role in angiotensin II-induced cardiac hypertrophy and remodeling[J]. CircRes.2003,93:874-883.
[18]郑伟.苦味酸天狼猩红染色在心脏胶原纤维定量分析中的应用[J].福建医科大学学报.1996,35(2):225.
[19]MeCullough PA. Coronary artery disease[J]. Clin JAm Soc Nephrol.2007,2(3): 611-616.
[20]Aoyagi T, Nakamura F, Tomaru T, et al. Beneficial effects of pitavastatin, a 3-hydroxy-3-methylglutaryl. coenzyme a reductase inhibitor,on cardiac function in ischemic and nonischemic heart failure[J]. Int Heart J.2008,49(1):49-58.
[21]Murray AJ, Edwards LM, Clarke K. Mitochondria and heart failure[J]. Curr Opin Clin Nutr Metab Care.2007,10(6):704-711.
[22]Qin F, Liang MC, Liang CS.Progressive left ventricular remodeling, myocyte apoptosis, and protein signaling cascades after myocardial infarction in rabbits[J]. Biochim Biophys Acta.2005,1740(3):499-513.
[23]Petrovic D. Cytopathological basis of heart failure-cardiomyocyte apoptosis, interstitial fibrosis and inflammatory cell response [J]. Folia Bi01.2004,50(2): 58-62.
[24]戴闺柱.心力衰竭生物学治疗的现状和展望.中华心血管病杂志,2005,33(10):873-4.
[25]Davis MJ, A macro and micro view of coronary vascular insult in ischemic heart disease.Circulation,1990,82(suppl Ⅱ):1138-46.
[25]陈灏珠译.心脏病学[M].第五版.北京:人民卫生出版社,2001;1084-5.
[27]Swynghedauw B,Molecular mechanisms of myocardial remodeling.Physiol Rev 1999,79:215-62.
[285]Wang J,Guo X,Dhalla NS. Modification of myosin protein and gcnecxprcssion in tailing hearts due to myoca8.ial infarction by enalapril or Losartan. Biochim Biophys Acta,2004,1690(2):177-84.
[29]Huang Y, Liu H, Li Y. Alterations in myosin heavy chain isoform gene expression during the transition from compensatory hypertrophy to congestive heart failure in rats. Chin Med J (EngL).2001,114:183-5.
[30]吴扬,刘霞。卡托普利防治心肌肥厚效应与心肌肌球蛋白重链基因表达及儿茶酚胺氧自由基代谢的关系。临床心血管病杂志,2003,19(2):103-5.
[31]Patel R, Nagueh SF, Tsybouleva N, et al. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy [J]. Circulation,2001,104: 317.
[32]Martin G, Duez H, Blanquart C, et al. Statin-induced inhibition of the Rho-signaling pathway activates PPARaand induces HDI apoA-I[J]. J Clin Invest,2001,107:1423.
[33]Lec TM. Chou TF. Tsai CH. Effects of pravastatin on cardlomyocyte hypertrophy and ventricular vulnerability in normolipidemie rats after myocardial infarction[J]. J Mol Cell Cardiol,2003,35(12):1449-1459.
[34]Nahrendorf M, Hu K, Hiller KH, et al. Impact of hydroxymethylglutaryl coenzyme a reductase inhibition on left ventricular remodeling after myocardial infarction:an experimental serial cardiac magnetic resonance imaging study[J]. J Am Coil Cardiol.2002,40(9):1695-1700.
[35]Palojoki E,Saraste A, Eriksson A,et al. Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats.Am J Physiol Heart Circ Physiol, 2001; 280:H2726-31.
[36]Kajstura J, Cheng W, Reiss K, et al. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab Invest,1996, 74(1):86-91.
[37]Ruixing Y, Dezhai Y, Hai W, et al. Intramyocardial injection of vascular endothelial growth factor gene improves cardiac performance and inhibits cardiomyocyte apoptosis[J]. Eur J Heart Fail.2007,9(4):343-351.
[38]Biondi-Zoccai GG, Abbate A, Vasaturo F, et al. Increased apoptosis in remote Non-infarcted myocardium in multivessel coronary disease[J]. Int J Cardi01.2004,94(1):105-110.
[39]Schwarz K, Simonsi G Yu X, et al. Apoptosis at a distance:remote activation of caspase-3 occurs early after myocardial infarction [J]. Mol Cell Biochem, 2006,281(1-2):45-54.
[40]Abbate A, Biondi-Zoccai GGL, Bussani R, et al. Increased myocardial apoptosis in patients with unfavorable left ventricular remodeling and early symptomatic post-infarction heart failure. J Am Coil Cardiol,2003,41:753-60.
[41]Wayman NS, Ellis BL, Thiemermann C, et al. Simvastatin reduces infarct size in a mode of acute myocardial ischemia and reperfusion in the rat[J]. Med Sci Monit.2003,9(5):BR155-159.
[42]樊爱英,韩子明,张贺.洛伐他汀对肾硬化大鼠细胞凋亡的影响.[J]实用儿科临床杂志.2004,19(7):572-574.
[43]Spinal FG. Matrix medtalloproteinases:regulation and dysregulation in the failing heart. Circ Res 2002,90(5):520-30.
[44]Weber KT. Extracellular matrix remodeling in heart failure:a role for de novo angiotension Ⅱ generation. Circulation,1997,96:4065-82.
[45]郭张强,廖玉华,程翔等.心肌梗死大鼠心室重塑的动态观察[J].分子与细胞免疫学.2006,22:1075-1078.
[46]Wei S, Chow LT,Sham IO, et al. Left and right ventricular collagen type 1/3 ratios and remodeling post myocardial infarction. J Card Fail,1999,5(2): 117-126.
[47]Bauersaehs J, Galuppo P, Fraeearollo D et al. Improvement of left ventrieular remodeling and function by hydroxymet hylglutaryl coerzyme a reduetase inhibition with cerivastatin in rats with heart failure after myocardial infarction. Circulation,2001,104(9):982-985.
[48]Hayashidani s. Tsutsni H, Shiomi T, et al. Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductasc inhibitor, attenuates left ventricular rcmedeftug and failure after experimental myocardial infarction[J]. Circulation,2002,105(7):868-873.
[49]Li TS, Takahashi M, Suzuki R,et al. Pravastatin improves remodeling and cardiac function after myocardial infarction by an antiinflammatory mechanism rather than by the induction of angiogenesis[J]. Ann Thorac Surg,2006,81(6): 2217-25.
[50]Bonnema DD, Webb CS, Pennington WR, et al. Effects of age on plasma matrix metalloproteinases(MMPs)and tissue inhibitor of metalloproteinases(TIMPs). Card Fail,2007,13(7):530-540.
[51]Hayashidani S,Tsutsui H, IkeuchiM, et al. Targeteddeletionof MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial inarction[J]. AmJ Physiol Heart Circ Physiol,2003,285(3):H1229-H1235
[52]Deten A, Hohl A, Leicht M. Changes in extracellularmatrix and in transforming growth factor beta isoforms after coronary artery ligation in rats[J]. J Mol Cell Cardiol,2001,33(6):1191-1207.
[53]Bruggink AH, Oosterhout MF, Jonge ND, at al. Etracellular matrix remodeling in canine and mouse myocardial infarcts[J]. J Heart Lung Transplant,2006,25 (9):1091-1098.
[54]Peterson JT, Li H, Dillon L, at al. Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat[J]. Cardiovascular Research,2000,46:307-315.
[55]Mukhejee R, Brinsa TA, Dowdy KB, at al. Myocardial infarct expansion and matrix metalloproteinase inhibition [J]. Circulation,2003,107:618.
[56]Kelly D, Khan S, Cockerill G, et al. Circulating stromelysin-1(MMPs):a novel predictor of LV dysfunction, remodeling and all-cause mortality after acute myocardial infarction. Eur Heart Fail,2008,10(2):133-139.
[57]Tyagi SC, Srech KG, Srinivasa RA, et al. Extracellular matric regulation of metalloprOteinase and antiproteinase in human heart fibroblast cells. J Cell Phys, 1996,167(1):137.
[58]Roten L, Nemoto S, Simsic J, et al. Effects of gene deletion of the tissue inhibitor of the matrix metalloproteinase-type 1(TIMP-1)on leftventricular geometry and function in mice. J Mol Cell Cardiol,2000,32:109-120.
[59]Visse R. Nagase H. Matrix metalloproteinases and tissue inhibitors of matalloproteinases:structure, function, and biochemistry. Circ Res,2003, 92(8):827-839.
[60]Hayashidani S, Tsutsui H, Shiomi T. el al. Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction[J]. Circulation,2002,105:868.
[61]Sironi L, Gianazza E, Gelosa P, Guerrini U, Nobili E, Gianella A, Cremonesi B, Paoletti R, Tremoli E. Rosuvastatin, but not simvastatin, provides end-organ protection in stroke-prone rats by antiinflammatory effects. Arterioscler Thromb Vase Biol 2005,25:598-603.
[62]Di Napoli P,Taccardi AA,Grilli A,De Lutiis MA,Barsotti A,Felaco M,De Caterina R.Chronic treatment with resuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injure in rat hearts. Cardiovase Res 2005,66:462-71.
[1]Majpm N G, O Roke, Codd M B, et al. Hospital mortality of acute myoadrial inf arction in the thormboltyicvear[J]. Heart,2005,81(3):478-482.
[2]Vannan MA, Taylor DJE. Ventricular remodeling after myocardial infarction. Br Heart J,1992,68:257-259
[3]Korup E, Dalsgaard D, Nyvad O, et al. Comparison of degrees of left ventricular dilation within three hours and up to six days after onset of first acute myocardial infarcion[J].Am J Cardiol,1997,80(4):449-453.
[4]Zimmerman SD, Criscione J, Covell JW. Remodeling in myocardium Adjacent to an infarction in the pig left ventricle[J]. Am J Cardiol,1997, (84):449-453.
[5]Mittmann C,EschenhagenT,Scholtz H.Cellular and molecular aspects of contractile dysfunction in heart failure.Cardiovasc Res 1998,39:267-175
[6]Baig MK, Mahon N,Mckenna WJ,et al.The pathophysiology of advanced heart failure. Am Heart,1998,135(6, part2):216-30.
[7]Maan DL.Mechanisms and models in heart failure.Circulation,1999,100(9): 999-1008.
[8]Siragy H. Angiotensin Il receptor blockers:review of the binding characterististics [J].Am J Cadliol 2004,84(10A):3S-8S..
[9]Sun Y, John Zhang JQ, Zhang J, et al. Cadiac remodeling byFibrous tissue after infarcion in rats[J]. J Lab Med,2000,135(4):316-323.
[10]Spyrou N, Rosen SD, Fath-Ordoubadi F, et al. Myocardial betaadrenoceptor density one month after acute myocardial infarction predicts left ventricular volumes at six months[J]. J Am Coll Cardil,2000,36(7):2072-2080.
[11]Silvestre JS, RoberV,Heymes C, et al. J Biol Chem,1998;273:4883-91.
[12]顾复生.醛固酮对心力衰竭的有害作用与醛固酮(受体)拮抗剂.中国循环杂志,2002,17:264-266.
[13]Romanic AM, Burns-Kurtis CI, Gout B, et al. Matrixetalloproteinase expression in cardiac myocytes following myocardial infarction in the rabbit[J]. Life Sci, 2001,68(7):799-814.
[14]Lalu MM, Csonka C, Giricz Z. Preconditioning decreases Ischemia/reperfusion-induced release and actiatvion of matrix metalloporoteinse-2[J]. Biochem Biophys Res Cmomun,2002,296(4): 937-941.
[15]Visse & Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases:structure, function,and biochemistry. Circ Res,2003,92(8): 227-239.
[16]Iwanaga Y,Aoyama T, Kihal'a Y, et al. Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypemophy to heart failure in hypertensive rats. JACC,2002,8: 1385-1391.
[17]张怀勤,张恩光,徐力新等。基质金属蛋白酶对大鼠心肌梗死后心室重塑的影响.中华心血管病杂志.2003.31:223-225.
[18]Bruggink AH.Osterhout MF.Jonge ND.et al.Extracellular matrix remodeling in canine and mouse myocardial infarcts[J].J Heart Lung Transplant,2006,25 (9): 1091-1098.
[19]Romanic A,Burns-Kurtis C, Gout B.el al. Matrix metalloproteinase expression in cardiac myocytes following myocardial infarction in the rabbit. Life Sci,2001, 68:799-814.
[20]Mukhcljee R, Brinsa T,Dowdy K. et al. Myocardial infarct expansion and matrix metalloproteinase inhibition. Circulation,2003,107:618-625.
[21]Peterson JT, Li H, Dillon L, et al. Evolution of matrix metalloprotease and tissue inhibitor expression during heart failure progression in the infarcted rat[J]. Cardiovascular Research,2000,46:307-315
[22]Herpel E, Pritsch M, Koch A et al. Interstitial fibrosis in the heart:differences in extracellular matrix proteins and matrix metalloproteinases in end-stage dilated, ischaemic and valvular cardiomyopathy. Histopathology,2006,48: 736-747.
[23]Picard F, Brehm M, Fassbach M, et al. Increased cardiac mRNA expression of matrix metalloproteinase-1(MMP-1)and its inhibitor(TIMP-1) in DCM patients. Clin Res Cardiol,2006,95:261-269.
[24]Roten L, Nemoto S, Simsic J, et al. Effects of gene deletion of the tissue inhibitor of the matrix metalloproteinase-type 1 (TIMP-1)on left ventricular geometry and function in mice[J]. J Mo 1 Cell Cardiol,2000,32:109-120.
[25]Abbate A, Biondi Zoccai GG Bussani R, et al. Increased myocardial apoptosis in patients with unfavorable left ventricular remodeling and early symptomatic post-infarction heart failure[J1. J Am Coil Cardiol,2003,41(5):753-760.
[26]Saitoh T, Nakajima T, Kawahara K. Possible involvement of apoptotic death of myocytes in left ventricular remodeling after myocardial infarction. Jpn J Physiol,2003,53(3):247-252.
[27]O hara Y,Hiasa Y,Hosokawa S et al. Impact of hydroxyl methylglutaryl coenzyme A reductase inhibition on left yentricular remodeling in patients with acute anterior myocardial infarction after primary coronary angioplasty. Int Heart J.2005,46(6):987-995.
[28]陈春红,尹博英.阿托伐他汀对急性心肌梗死患者心室重构及心功能的影 响.山东医药,2008,48(7):18-20.
[29]Andrew C。Jessica KT, Brandy W et al. Mechanisms of statin mediated inhibition of small G-protein function. J Biol Chem,2005,280:34202-34209.
[30]Ciro I, Emilio DL, Cinzia P et al. Hydroxy methylglutaryl coenzyme A reductase inhibitor simvastatin prevents cardiac hypertrophy induced by pmssum overload and inhibits P21 ras activation. Circulation.2002,106:2118-2124.
[30]Mita S, Kobayashi N, Yashida K etal. Cardiop rotectivemechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats. J Hypertem,2005,23:87-96.
[31]Kino MF, Susumu A。Yasuhiro M et al. HMG-CoA reductase inhibitor fluvastatin prevents angiotensin-Ⅱ induced csrdiac hypertrophy via Rho kinase and inhibition of cyclin D1. Life Sci,2006,79:1380-1390.
[32]Toshihiro I, Kotaro T, Tomotake T et al. Downregulation of Angiotensin Ⅱ type 1 reeeptor by hydrophobie 3-hydroxy-3-methylglutaryl cocnzyme A reductase inhibitors in vascular smooth muscle cells. Arterioscler Thromb Vase Biol,2001, 21(12):1896.
[33]王安才,成蓓,谢晓竞等.阿托伐他汀对自发性高压大鼠心室重构的影响.中国临床药理学与治疗学,2004,9(8):880-889。
[34]Danieh F, Widder JD, Paolo G et al. Improvement in left ventricular remodeling by the endothelial nitric oxide synthase enhancer AVE9488 after experimental myocardial infarction. Circulation,2008; 118:818-827.
[35]李爱国,赵连友,郑强荪.阿托伐他汀对成年大鼠心肌成纤维细胞分泌内皮素1及一氧化氮合酶/一氧化氮系统活性的影响.医学研究生报,2003,16(10):733-739.
[36]Minoru S, Hisakazu 0, Kyosuke T et al. Requirement of Racl in the development of cardiac hypertrophy. PNAS,2006,103:7432-7437.
[37]Planavila A, Laguna JC, Vazquez Carrera M. A torvastatin improves peroxisome proliferator activated receptor signaling in cardiac hypertrophy by preventing nuclear factor-kappaB activation. Bioehim Biophys Acts.2005, 1687(123):76-83.
[38]Zhang J, Cheng X, Liao YH et al. Simvastatin regulates myocardial cytokine expression and improves ventrieular remodeling in rats after acute myocardial infarction,Cardiovase Drugs Ther,2005,19(1):13-21.
[39]何文凯.阿托伐他汀钙对自发性高血压大鼠血压及左室功能的影响.广州医学院学报,2006,34(2):9-12
[40]Bauersaehs J, Galuppo P, Fraeearollo D et al. Improvement of left ventrieular remodeling and function by hydroxymet hylglutaryl coerzyme a reduetase inhibition with cerivastatin in rats with heart failure after myocardial infarction. Circulation,2001,104(9):982-985.
[41]Martin J, Denver R, Bailey M et al. In vitro inhibitory effects of atorvastatin on cardiac fibroblasts:implications for ventricular remodelling. Clin Exp Pharmaeol Physiol,2005,32(9):697.
[42]Hayashidani S, Tsutsui H, Shiomi T et aL. Fluvastatin, a 3-hy2droxy-3-met hylglutaryl eoenzyme a reduetase inhibitor, attenuates left ventfieular remodeling and failure after experimental myocardial infarction. Circulation,2002,105(7): 868-873.