慢性心房颤动电重构和结构重构机制的研究
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摘要
研究背景 心房颤动(简称房颤)是最常见的具有临床意义的心律失常,发病率随年龄增长而增加。随着我国人口老龄化,房颤的防治作为一个难题更加突出。房颤的治疗效果有赖于对其发生和维持机制的深入了解,而合适的房颤动物模型是研究其发生机制的基础。因此,建立病理生理基础与临床情况相似的房颤动物模型对于其发生机制和防治的研究具有重要意义。房颤具有自身延续性,在这一发展过程中心房肌细胞结构、心房肌间质和心房血流动力学发生了改变,称为房颤心房结构重构。人们已经认识到心房结构重构在房颤的发生和维持中起重要作用,但有关心房颤时心房结构重构的分子机制和影响因素仍不明确。
正常情况下,维持心脏结构和功能完整的心肌细胞外基质(extracellular matrix,ECM)处于合成与降解的动态平衡之中。基质金属蛋白酶(matrix metalloproteinase,MMPs)和组织型基质金属蛋白酶抑制因子(tissue inhibitor of metalloproteinase,TIMPs)是影响心脏细胞外基质蛋白降解的主要因素。对衰竭心脏的研究发现,MMPs活性升高导致进行性心室扩大。基础研究表明心房组织中亦存在MMPs/TIMPs系统,但慢性房颤时MMPs/TIMPs系统激活是否与心房扩大有关未见相关报道。
临床研究表明,房颤时心房肌局部肾素—血管紧张素系统(renin angiotensin system,RAS)激活是房颤患者心房肌纤维化的重要机制。但在慢性房颤模型中RAS系统激活与结构重构的关系仍不清楚。心衰心肌纤维化时,胶原链断裂并被缺少连接的胶原所取代,这种ECM的重构是由MMPs活性调节,由此推测RAS系统激活导致的细胞外基质纤维堆积和MMPs/TIMPs系统介导的细胞外基质降解之间可能存在联系。
整合素(integrin)是粘附分子的一种,其中的整合素β_1亚组主要影响细胞与胶原、纤维连接蛋白和层粘连蛋白的粘附,为心肌细胞的相互联系和排列提供
Background Atrial fibrillation (AF) is one of the most common sustained tachyarrhythmia in clinical practice. The incidence increased with aging. Atrial fibrillation is not only accompanied by stroke, but also an independent risk factor to predict the morbidity. However, current treatment modalities for AF are far from satisfactory. The underling mechanism of AF remains unclear, which make the pharmacologic therepy is still challenges. It is important to establish an atrial fibrillation model to investigate the mechanism underling AF. It is well established that AF cause atrial structural remodeling leading to maintenance of AF. The molecular basis for the development of atrial structural remodeling of atrial fibrillation is still a matter of debate. Its understanding, however, could have an important therapeutic impact.Extracellular matrix (ECM) contributes to the maintenance of cardiac geometry and the structural alignment of adjoining myocytes. Matrix metalloproteinase (MMPs) and tissue inhibitor of metalloproteinase (TIMPs) are responsible for extracellular collagen degradation and synthesis. MMPs activation can cause left ventricular dilation in end stage CHF. Basic reseach find MMPs/TIMPs are also presented in atrial tissue. Whether there is possible relationship between MMPs/TIMPs activation and atrial enlargement of chronic AF remains unclear.It is well known that local renin-angiotensin system (RAS) is involved in atrial myocardial fibrosis in AF patients. But there are still in debating on MMPs activation influencing atrial structural remodeling in chronic AF model. MMPs regulates ECM remodeling, so there are maybe relationship between ECM accumulation attributing to RAS activation and degradation attributing to MMPs/TIMPs.Integrin β_1 is one of the adhesion molecular, which regulates cell-cell and cell-matrix interactions. Its expression can maintain myocardial structural integrity. The role of integrin β_1 in atrial structural remodeling is deserved to investigate. It will help us to understand the interaction of myocytes and ECM in atrial structural remodeling of AF.
Objective(1) To establish a rapid atrial pacing induced atrial fibrillation model;(2) To elucidate the characteristic of unltrastructure, cardiac extracellular matrix, atrial geometry and function of atrial tissue when atrial fibrillation is persistent;(3) To investigate the role of MMPs/TIMPs , integrin P 1 and renin angiotensin system in atrial structural remodeling and their relationships;(4) To find the activators and influnce factors of MMPs/TIMPs and RAS;(5) To compare the difference between left and right atrial remodeling. Methods(1) Establish a canine chronic atrial fibrillation model by rapid atrial pacing.(2) Echocardiography was performed to determined the changes of biatrial dimension before and after 8 weeks pacing. Mitral and tricuspid regurgitation were also viewed by colour Doppler flow image during pacing.(3) Left ventricular end diastolic pressure, right ventricular end diastolic pressure, right atrial pressure were assessed by cardie catheterization before and after 8 weeks rapid atrial pacing.(4) Angiotensin II concentration in atrial tissue was determined by radio-immunity.(5) The content of calcium was assessed by spectrocomparator in atrial myocardium.(6) HE stain and trichrome stain were preformed to observe myocyte structure and determine the content of collagen in atrial myocardium.(7) Ultrastructural changes of left and right atrial tissue both atrial fibrillation and control were observed by transmission electron microscopy.(8) The messenger ribonucleic acid(mRNA) level of angiotensin converting enzyme(ACE), integrin P ? matrix metalloproteinases-9(MMP-9) and tissue inhibitor of matrix metalloproteinase-l(TIMP-l) were measured by reverse transcription polymerase chain reaction(RT-PCR) and normalized to the mRNA level of P actin.(9) Immunohistochemistry was performed to determine the protein expression and distribution of MMP-1, MMP-9 and TBVIP-1 in myocytes.(10) Statistical analysis. All continuous data were expressed as means± 1 standard deviation, SPSS 10.0 for windows was used to analyze all data. Comparisons between
groups were performed with unpaired Student's t-te&t Comparisons of continuous variables among multiple groups were performed by single- factor ANOVA. Pearson's correlation coefficient (r) was used to determind the relation between groups. Mann-Whitney test was used to non-parameter. A value of P<0.05 was considered to be statistically significant. Results(1) AF model. Eleven anesthetized mongrel dogs underwent insertion of transvenous lead at the right atrial appendage that was continuously paced at 370-430 beat per minute for 8 weeks. Among those dogs, one had a sudden death after 12 hours pacing, one showed heart failure sympom after 4 weeks pacing and echocardiography showed thrombosis in right atrium, and pacemaker stop generating pulse in another dog at the end of study. Before rapid atrial pacing, AF was not induced in any dogs by programmed stimuli and burst pacing. After 8 weeks of continuous rapid atrial pacing, AF was occurred spontenously in 2 dogs (25%), sustained AF was induced in 4 dogs by programed stimuli (50%), and in 2 dogs by burst pacing (25%). It was shown that chronic atrial fibrillation model was successfully established.(2) None of dogs showed valvular regurgitation before rapid atrial pacing. Different extent of mitral and tricuspid regurgitation was viewed in all rapid atrial pacing (RAP) dogs at the end of study. In contrast, mild mitral regurgitation was occurred in one control dog. Compared with control and before pacing, left atrial dimension and right atrial area enlargement was documented in RAP dogs. There were not significant changes of atrial dimension in control dogs.(3) There were no significant difference in left ventricular end diastolic pressure (LVEDP) and right atrial pressure between RAP and control dogs before pacing (LVEDP: 12.00±6.07 VS 9.00 + 5.47; right atrial pressure^.17 + 2.52 VS 4.95 + 3.24, P>0.05 respectively). Compared with control dogs, LVEDP and right atrial pressure of RAP dogs elevated markedly after 8 weeks continuous rapid atrial pacing( LVEDP: 14.87 + 2.79 VS 10.00+3.95; right atrial pressure: 7.09+ 1.13 VS 4.50+1.51, P <0.01, respectively).(4) Compared with control, the content of calcium inleft and right atrial myocardium was elevated by 46.39% and 36.17% ( LA: 35.09+4.93 VS 23.97+4.50; RA: 37.68+10.45 VS 27.67 + 4.46, P < 0.001, 0.05, respectively). Content of
magnesium in left atrial tissue was decreased by 9.11% (61.69 + 6.73 VS 67.87 + 5.85 P <0.05), whereas it had no statistical significance in right atrial tissue(56.45 +1.64 VS 58.42 + 5.15 P>0.05).The content of calcium had no significant difference between left and right atrial myocardium in both control and RAP dogs.(5) Compared with control, the level of angiotensin II of both atrial myocardium was significantly increased in RAP dogs. The content of angiotensin II of left atrial myocardium is markedly increased than that of right atrium in control dogs. Whereas there was no significant difference between left and right atrial tissue in RAP dogs.(6) Histologic examination. Atrial myocardium sections from controls were normally structured cardiomyocytes, which were surrounded by a small amount of connective tissue. Sarcomeres were present throughout cytoplasm of cardiomycytes. Sections from RAP dogs showed severe myolysis. Early myocardial hypertrophy was observed in both atrial tissue from rapid atrial pacing dogs. Cardiomyocytes were disarrangement and connective tissue was accumulated. Some cardiomyocytes were surrounded by collagen tissue and myofilament was disrupted. Masson stain showed that collagen tissue was appropriate arranged among cardiomyocytes in control samples. Samples from RAP dogs showed, however, collagen tissue increased markedly, and disrupted in some area.(7) Electron microscopy. At the ultrastructural level, atrial myocytes from controls showed a highly organized sarcomeric structure with rows of uniformly sized mitochondria in between. Atrial granules were mainly confined to the perinuclear area. A typical distribution of heterochromatin in the form of clusters at the nuclear memrane was present in all cardiomyocyte nuclei. Intercalated disk were normally structured. Atrial myocytes from RAP dogs showed characteristic changes as below: ?Contractile material was depleted(myolysis). The disapperance of sarcomeres was often limited to the vicinity of the nucleus but also frequently involved the entire cytosol, in which only fragments of sarcomeres were present. ?Huge amount of glycogen filled the myolytic space in almost all cells that underwent myolysis. in some area, even accumulated like" glycogen lake"? Typical changes in size and shape of mitochondria were seen in area delepted of sarcomeres. Many mitochodria had become elongated. (5) The heterochromatin was dispersed uniformly throughout the nucleoplasm. ? Intercalated disk were disrupted in some areas and indistinct. (7) the sarcoplasmic reticulum was
partially destroyed and showed edema. Although these abnomalities were seen in both the left and right atria, tissue from the left atrium displayed significantly more abnomalities than did the tissue from right atrium. ?Atrial granules were increased and scattered widely.(8) Results of RT-PCR. ?Compared with control, the mRNA level of ACE of left and right atrial myocardium from RAP dogs was significantly increased by 54.54% and 45%( LA: 0.68+0.11 VS 0.44 + 0.19; RA: 0.29+0.08 VS 0.20 + 0.01, P <0.05).The mRNA level of ACE of left atrial tissue was markedly increased compared with that of right atrium in controls and RAP dogs.(2)Compared with control, the mRNA level of integrin P , from RAP dogs was increased by 95.35% (0.84+0.33 VS 0.43±0.02, P<0.01) in left atrial tissue but had no significant changes in right atrial tissue (0.34+ 0.09 VS 0.35 + 0.02, P>0.05). The mRNA level of integrin P , of left atrial tissue was markedly increased compared with that of right atrium in controls and RAP dogs. (3) Compared with control, the mRNA levels of MMP-9 in left and right atrial myocardium from RAP dogs were elevated significantly by 45.00% and 109.09% while TIMP-1 were elevated 46.67% and 71.43%, respectively. (MMP-9: LA 0.29+0.06 VS 0.20+ 0.03, RA 0.23 + 0.07 VS 0.11+0.009; TIMP-1: LA 0.22 + 0.02 VS 0.15 + 0.01, RA 0.12+0.02 VS 0.07+0.01, all P<0.01).However, there were no significant changes of the ratio of MMP-9/TIMP-l.The mRNA level of MMP-9 and TIMP-l of left atrial tissue were markedly increased compared thoses of right atrium in control and RAP dogs.(9) Pearson correlation analysis. Left atrial dimension was positively correlated with the mRNA level of ACE, MMP-9, TIMP-1 and the concentration of calcium in atrial myocardium (P<0.01). Right atrial area was only positively correlated with the mRNA level of ACE(P<0.05). LVEDP was correlated with the mRNA level of MMP-9(P<0.05) while right atrial pressure was correlated positively with the mRNA level of TMP-l(P<0.01).00) Immunohistochemistry Protein expression of MMP-1, MMP-9 from RAP atrial tissue were more significant than that from control tissue. Whereas protein expression of TIMP-1 from RAP atrial tissue was markedly less than that from controls. Conclusion(1) Chronic atrial fibrillation model was successfully established by rapid atrial
正常情况下,维持心脏结构和功能完整的心肌细胞外基质(extracellular matrix,ECM)处于合成与降解的动态平衡之中。基质金属蛋白酶(matrix metalloproteinase,MMPs)和组织型基质金属蛋白酶抑制因子(tissue inhibitor of metalloproteinase,TIMPs)是影响心脏细胞外基质蛋白降解的主要因素。对衰竭心脏的研究发现,MMPs活性升高导致进行性心室扩大。基础研究表明心房组织中亦存在MMPs/TIMPs系统,但慢性房颤时MMPs/TIMPs系统激活是否与心房扩大有关未见相关报道。
临床研究表明,房颤时心房肌局部肾素—血管紧张素系统(renin angiotensin system,RAS)激活是房颤患者心房肌纤维化的重要机制。但在慢性房颤模型中RAS系统激活与结构重构的关系仍不清楚。心衰心肌纤维化时,胶原链断裂并被缺少连接的胶原所取代,这种ECM的重构是由MMPs活性调节,由此推测RAS系统激活导致的细胞外基质纤维堆积和MMPs/TIMPs系统介导的细胞外基质降解之间可能存在联系。
整合素(integrin)是粘附分子的一种,其中的整合素β_1亚组主要影响细胞与胶原、纤维连接蛋白和层粘连蛋白的粘附,为心肌细胞的相互联系和排列提供
Background Atrial fibrillation (AF) is one of the most common sustained tachyarrhythmia in clinical practice. The incidence increased with aging. Atrial fibrillation is not only accompanied by stroke, but also an independent risk factor to predict the morbidity. However, current treatment modalities for AF are far from satisfactory. The underling mechanism of AF remains unclear, which make the pharmacologic therepy is still challenges. It is important to establish an atrial fibrillation model to investigate the mechanism underling AF. It is well established that AF cause atrial structural remodeling leading to maintenance of AF. The molecular basis for the development of atrial structural remodeling of atrial fibrillation is still a matter of debate. Its understanding, however, could have an important therapeutic impact.Extracellular matrix (ECM) contributes to the maintenance of cardiac geometry and the structural alignment of adjoining myocytes. Matrix metalloproteinase (MMPs) and tissue inhibitor of metalloproteinase (TIMPs) are responsible for extracellular collagen degradation and synthesis. MMPs activation can cause left ventricular dilation in end stage CHF. Basic reseach find MMPs/TIMPs are also presented in atrial tissue. Whether there is possible relationship between MMPs/TIMPs activation and atrial enlargement of chronic AF remains unclear.It is well known that local renin-angiotensin system (RAS) is involved in atrial myocardial fibrosis in AF patients. But there are still in debating on MMPs activation influencing atrial structural remodeling in chronic AF model. MMPs regulates ECM remodeling, so there are maybe relationship between ECM accumulation attributing to RAS activation and degradation attributing to MMPs/TIMPs.Integrin β_1 is one of the adhesion molecular, which regulates cell-cell and cell-matrix interactions. Its expression can maintain myocardial structural integrity. The role of integrin β_1 in atrial structural remodeling is deserved to investigate. It will help us to understand the interaction of myocytes and ECM in atrial structural remodeling of AF.
Objective(1) To establish a rapid atrial pacing induced atrial fibrillation model;(2) To elucidate the characteristic of unltrastructure, cardiac extracellular matrix, atrial geometry and function of atrial tissue when atrial fibrillation is persistent;(3) To investigate the role of MMPs/TIMPs , integrin P 1 and renin angiotensin system in atrial structural remodeling and their relationships;(4) To find the activators and influnce factors of MMPs/TIMPs and RAS;(5) To compare the difference between left and right atrial remodeling. Methods(1) Establish a canine chronic atrial fibrillation model by rapid atrial pacing.(2) Echocardiography was performed to determined the changes of biatrial dimension before and after 8 weeks pacing. Mitral and tricuspid regurgitation were also viewed by colour Doppler flow image during pacing.(3) Left ventricular end diastolic pressure, right ventricular end diastolic pressure, right atrial pressure were assessed by cardie catheterization before and after 8 weeks rapid atrial pacing.(4) Angiotensin II concentration in atrial tissue was determined by radio-immunity.(5) The content of calcium was assessed by spectrocomparator in atrial myocardium.(6) HE stain and trichrome stain were preformed to observe myocyte structure and determine the content of collagen in atrial myocardium.(7) Ultrastructural changes of left and right atrial tissue both atrial fibrillation and control were observed by transmission electron microscopy.(8) The messenger ribonucleic acid(mRNA) level of angiotensin converting enzyme(ACE), integrin P ? matrix metalloproteinases-9(MMP-9) and tissue inhibitor of matrix metalloproteinase-l(TIMP-l) were measured by reverse transcription polymerase chain reaction(RT-PCR) and normalized to the mRNA level of P actin.(9) Immunohistochemistry was performed to determine the protein expression and distribution of MMP-1, MMP-9 and TBVIP-1 in myocytes.(10) Statistical analysis. All continuous data were expressed as means± 1 standard deviation, SPSS 10.0 for windows was used to analyze all data. Comparisons between
groups were performed with unpaired Student's t-te&t Comparisons of continuous variables among multiple groups were performed by single- factor ANOVA. Pearson's correlation coefficient (r) was used to determind the relation between groups. Mann-Whitney test was used to non-parameter. A value of P<0.05 was considered to be statistically significant. Results(1) AF model. Eleven anesthetized mongrel dogs underwent insertion of transvenous lead at the right atrial appendage that was continuously paced at 370-430 beat per minute for 8 weeks. Among those dogs, one had a sudden death after 12 hours pacing, one showed heart failure sympom after 4 weeks pacing and echocardiography showed thrombosis in right atrium, and pacemaker stop generating pulse in another dog at the end of study. Before rapid atrial pacing, AF was not induced in any dogs by programmed stimuli and burst pacing. After 8 weeks of continuous rapid atrial pacing, AF was occurred spontenously in 2 dogs (25%), sustained AF was induced in 4 dogs by programed stimuli (50%), and in 2 dogs by burst pacing (25%). It was shown that chronic atrial fibrillation model was successfully established.(2) None of dogs showed valvular regurgitation before rapid atrial pacing. Different extent of mitral and tricuspid regurgitation was viewed in all rapid atrial pacing (RAP) dogs at the end of study. In contrast, mild mitral regurgitation was occurred in one control dog. Compared with control and before pacing, left atrial dimension and right atrial area enlargement was documented in RAP dogs. There were not significant changes of atrial dimension in control dogs.(3) There were no significant difference in left ventricular end diastolic pressure (LVEDP) and right atrial pressure between RAP and control dogs before pacing (LVEDP: 12.00±6.07 VS 9.00 + 5.47; right atrial pressure^.17 + 2.52 VS 4.95 + 3.24, P>0.05 respectively). Compared with control dogs, LVEDP and right atrial pressure of RAP dogs elevated markedly after 8 weeks continuous rapid atrial pacing( LVEDP: 14.87 + 2.79 VS 10.00+3.95; right atrial pressure: 7.09+ 1.13 VS 4.50+1.51, P <0.01, respectively).(4) Compared with control, the content of calcium inleft and right atrial myocardium was elevated by 46.39% and 36.17% ( LA: 35.09+4.93 VS 23.97+4.50; RA: 37.68+10.45 VS 27.67 + 4.46, P < 0.001, 0.05, respectively). Content of
magnesium in left atrial tissue was decreased by 9.11% (61.69 + 6.73 VS 67.87 + 5.85 P <0.05), whereas it had no statistical significance in right atrial tissue(56.45 +1.64 VS 58.42 + 5.15 P>0.05).The content of calcium had no significant difference between left and right atrial myocardium in both control and RAP dogs.(5) Compared with control, the level of angiotensin II of both atrial myocardium was significantly increased in RAP dogs. The content of angiotensin II of left atrial myocardium is markedly increased than that of right atrium in control dogs. Whereas there was no significant difference between left and right atrial tissue in RAP dogs.(6) Histologic examination. Atrial myocardium sections from controls were normally structured cardiomyocytes, which were surrounded by a small amount of connective tissue. Sarcomeres were present throughout cytoplasm of cardiomycytes. Sections from RAP dogs showed severe myolysis. Early myocardial hypertrophy was observed in both atrial tissue from rapid atrial pacing dogs. Cardiomyocytes were disarrangement and connective tissue was accumulated. Some cardiomyocytes were surrounded by collagen tissue and myofilament was disrupted. Masson stain showed that collagen tissue was appropriate arranged among cardiomyocytes in control samples. Samples from RAP dogs showed, however, collagen tissue increased markedly, and disrupted in some area.(7) Electron microscopy. At the ultrastructural level, atrial myocytes from controls showed a highly organized sarcomeric structure with rows of uniformly sized mitochondria in between. Atrial granules were mainly confined to the perinuclear area. A typical distribution of heterochromatin in the form of clusters at the nuclear memrane was present in all cardiomyocyte nuclei. Intercalated disk were normally structured. Atrial myocytes from RAP dogs showed characteristic changes as below: ?Contractile material was depleted(myolysis). The disapperance of sarcomeres was often limited to the vicinity of the nucleus but also frequently involved the entire cytosol, in which only fragments of sarcomeres were present. ?Huge amount of glycogen filled the myolytic space in almost all cells that underwent myolysis. in some area, even accumulated like" glycogen lake"? Typical changes in size and shape of mitochondria were seen in area delepted of sarcomeres. Many mitochodria had become elongated. (5) The heterochromatin was dispersed uniformly throughout the nucleoplasm. ? Intercalated disk were disrupted in some areas and indistinct. (7) the sarcoplasmic reticulum was
partially destroyed and showed edema. Although these abnomalities were seen in both the left and right atria, tissue from the left atrium displayed significantly more abnomalities than did the tissue from right atrium. ?Atrial granules were increased and scattered widely.(8) Results of RT-PCR. ?Compared with control, the mRNA level of ACE of left and right atrial myocardium from RAP dogs was significantly increased by 54.54% and 45%( LA: 0.68+0.11 VS 0.44 + 0.19; RA: 0.29+0.08 VS 0.20 + 0.01, P <0.05).The mRNA level of ACE of left atrial tissue was markedly increased compared with that of right atrium in controls and RAP dogs.(2)Compared with control, the mRNA level of integrin P , from RAP dogs was increased by 95.35% (0.84+0.33 VS 0.43±0.02, P<0.01) in left atrial tissue but had no significant changes in right atrial tissue (0.34+ 0.09 VS 0.35 + 0.02, P>0.05). The mRNA level of integrin P , of left atrial tissue was markedly increased compared with that of right atrium in controls and RAP dogs. (3) Compared with control, the mRNA levels of MMP-9 in left and right atrial myocardium from RAP dogs were elevated significantly by 45.00% and 109.09% while TIMP-1 were elevated 46.67% and 71.43%, respectively. (MMP-9: LA 0.29+0.06 VS 0.20+ 0.03, RA 0.23 + 0.07 VS 0.11+0.009; TIMP-1: LA 0.22 + 0.02 VS 0.15 + 0.01, RA 0.12+0.02 VS 0.07+0.01, all P<0.01).However, there were no significant changes of the ratio of MMP-9/TIMP-l.The mRNA level of MMP-9 and TIMP-l of left atrial tissue were markedly increased compared thoses of right atrium in control and RAP dogs.(9) Pearson correlation analysis. Left atrial dimension was positively correlated with the mRNA level of ACE, MMP-9, TIMP-1 and the concentration of calcium in atrial myocardium (P<0.01). Right atrial area was only positively correlated with the mRNA level of ACE(P<0.05). LVEDP was correlated with the mRNA level of MMP-9(P<0.05) while right atrial pressure was correlated positively with the mRNA level of TMP-l(P<0.01).00) Immunohistochemistry Protein expression of MMP-1, MMP-9 from RAP atrial tissue were more significant than that from control tissue. Whereas protein expression of TIMP-1 from RAP atrial tissue was markedly less than that from controls. Conclusion(1) Chronic atrial fibrillation model was successfully established by rapid atrial
引文
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26. Wouters L, Liu G-S, Flameng W, et al. Structural remodeling of atrial myocardium in patients with cardiac valve disease and atrial fibrillation. Exp Clin Cardiol, 2001,5:158-163
27. Boyden PA, Tilley LP, Pham TD, et al. Effects of left atrial enlargement on atrial transmembrane potentials and structure in dogs with mitral valve fibrosis. Am J Cardiol, 1982,49:1896-1908
28. Frustaci A, Chimenti C, Bellocci F, et al. Histological substrate of attrial biopsies in patients with lone atrial fibrillation. Circulation, 1997,96:1180-1184
29. Brundel BJM, Ausma J, van Gelder IC, et al. Calpain activity is related to ion-channel, structural and electrical remodeling in human paroxymal and persistent atrial fibrillation. Thesis. University of Groningen, Groningen, 2000
30. Ausma J, Wijffels M, Thone F, et al. Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation, 1997, 96:3157-3163
31. Leistad E, Aksnes G, Verbug E, et al. Atrial contractile dysfunction after short-term atrial fibrillation is reduced by verapamile but increased by BAY K8644. Circulation, 1996,93(9): 1747-1754
32. Pirolo JS, Hutchins GM, Moore GW. Myocyte vacuolization in infarct border zones is reversible. Am J Pathol, 1985,121: 444-450
33. Borg TK, Rubin K, Lundgren E, et al. Recognition of extracellular matrix components by neonatal and adult cardiac myocytes. Dev Biol, 1984,104:86-96
34. Mary-Rabine L, Albert A, Pham TD,et al.The relationship of human atrial cellular electrophysiology to clinical function and ultrastructure. Cir Res, 1983, 52: 188 - 199
35. Thijssen V, Ausma J, Borgers M. Structural remodeling during chronic atrial fibrillation: act of programmed cell survival. Cardiovasc Res, 2001,52:14-24
36. White CW, Jerver RE, Weiss HR,et al.The effect of atrial fibrillation on atrial pressure-volume and flow relationship. Circ Res,1982, 51:205-215
37. Van Wagoner DR, Pond AL, Lamorgese M, et al. Atrial L-type Ca2+ currents and human atrial fibrillation. Circ Res, 1999, 85(5): 428-36
38. Ausma J, Dispersyn GD, Duimel H, et al. Changes in ultrastructrual calcium distribution in goat atria during atrial fibrillation. J Mol Cell Cardiol, 2000, 32: 355 -364
39. Goette A, Staack T, Rocken C, et al. Increased expression of extracellular signal-regulated kinase and angiotensin -converting enzyme in human atria during atrial fibrillation. J Am Coll Cardiol, 2000:35:1669-1677
40. Goette A, Arndt M, Rocken C, et al. Regulation of angiotensin II receptor subtypes during atrial fibrillation in humans. Circulation, 2000,101:2678-2781
41. Rogg H, de Gasparo M, Graedel E, et al. Angiotensin II-receptor subtypes in human atria and evidence for alterations in patients with cardiac function. Eur Heart J, 1996,17:1112-1120
42. Asno K, Dutcher DL, Port JD, et al.Selective downregulation of the angiotensin II AT1-R receptor subtype in failing human ventricular myocardium. Circulation, 1997, 95:1193-1200
43. Matsubara H.Pathophysiological role of angiotensin II type receptor in cardiovascular and renal diseases. Circ Res,1998, 83:1182-1191
44. Robinson TF, Cohen-Gould L, Factor SM, et al. Structure and function of connective tissue in cardiac muscle: collagen types I and III in endomysial struts and pericellular fibers. Scanning Microsc, 1988, 2(2): 1005-1015.
45. Boixel C, Fontaine V, Rucker-Marin C, et al. Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat. J Am Coll Cardiol, 2003,42:336-344
46. Kuwahara F, Kai H, Tokuda K, et al. Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure- overloaded rats. Circulation, 2002, 106(1): 130-135.
47. Lijnen P, Petrov V. Antagonism of the renin-angiotensin-aldosterone system and collagen metabolism in cardiac fibroblasts. Methods Find Exp Clin Pharmacol. 1999, 21(3): 215-27
48. Ramires FJ, Sun Y, Weber KT. Myocardial fibrosis associated with aldosterone or angiotensin II administration: attenuation by calcium channel blockade. J Mol Cell Cardiol, 1998,30(3): 475-483
49. Tharaux PL, Chatxiantoniou C, Fakhouri F et al. Angiotensin II activates collagen I gene through a mechanism involving the MAP/ER kinase pathway. Hypertension, 2000,36,330-336
50. Varo N, Iraburu MJ, Varela M, et al. Chronic AT(1) blockade stimulates extracellular collagen type I degradation and reverses myocardial fibrosis in spontaneously hypertensive rats. Hypertension,2000, 35(6): 1197-1202.
51. Gampbell SE, Katwa LC. Angiotensin II stimulated expression of transforming growth factor beta-1 in cardiac fibroblasts and myofibroblasts. J Med Cell Cardiol, 1997,29(7): 1947-1958
52. Horiuchi M, Akishita M, Dxau VJ. Recent progress in angiotensin II type 2 receptor research in the cardiovascular system. Hypertension, 1999,33:613-621
53. Senbonmatsu T, Ichihara S, Price E Jr, et al. Evidence for angiotensin II type 2 receptor -mediated cardiac myocyte enlargement during in vivo pressure overload. J Clin Invest, 2000,106(3): R25-R29
54. Yamada H, Horiuchi M, Akishita M, et al. Regulation of vascular develoment and differentiation by angiotensin II type 2 receptor. Hypertension, 1997,30:470-475
55. Yamada T, Akishita M, Pollman M, et al. Angiotensin II type 2 receptor mediates vascular smooth muscle cell apoptosis and antagomize angiotensin type 1 receptor action: an in vitro gene transfer study. Life Sci, 1998,63:PL289-PL295
56. Dimmeler S, Rippmann V, Weiland U, et al. Angiotensin II induces apoptosis of human endothelial cells: protective effect of nitric oxide. Circ Res, 1997,81:970-976
57. Tsutsumi Y, Mataubara H, Ohkubo N, et al. Angiotensin II type 2 receptor is upregulated in human heart with interstitial fibrosia and cardiac fibroblasts are the major cell type for its expression. Circ Res, 1998,1035-1046
58. Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix matelloproteinase activity in cardiac fibroblasts. Am J Physiol (Cell Physiol), 2001,280(1): C53-C60
59. Kumaran C, Shivakumar K. Superoxide-mediated activation of cardiac fibroblasts by serum factors in hypomagnesemia. Free Radic Biol Med, 2001,31(7): 882-886
60. Li PF, Diez R, von Harsdorf R, et al. Superoxide induces apoptosis in cardiomyocytes, but proliferation and expression of transforming growth factor beta in cardiac fibroblast. FFBB-Lett, 1999,488:206-210
61. Korantzopoulos P, kolettis T, Siogas K, et al. Atrial fibrillation and eletrical remodeling: the role of inflammation and oxidative stress. Med Sci Moint, 2003, 9:RA225-229
62. Hsueh WA, Law RE, Do YS. Integrins, adhesion, and cardiac remodeling. Hypertension, 1998,31[1 part 2]: 176-180
63. Collo G, Srarr L, Quaranta V. A new isoform of the laminin receptor integrin alpha 7 betal is developmentally regulated in skeletal muscle. J Biol Chem, 1993, 268: 19019-19024
64. Fassler R, Rohwedel J, Malsterv V, et al. Differentiation and integrity of cardiac muscle cells are impaired in the absence of 尾 , integrin. J Cell Scien, 1996, 109:2989-2999
65. Lewis JM, Schwartz MA. Mapping in vivo associations of cytoplasmic proteins with integrin beta 1 cytoplasmic domain mutants. Mol Biol Cell, 1995,6:151-160
66. Arndt M, Lendeckel U, Rocken C, et al. Altered expression of ADAMs(A Disintegrin And Metalloproteinase) in fibrillation human atria. Circulation, 2002,105:720-725
67. Werb Z, Yan Y. A cellular striptease act. Science, 1998,282:1279-1280
68. Pechon J, Slack JL, Reddy P, et al. An essential role for ectodomain shedding in mammalian development. Science, 1998,282:1281-1284
69. Chen Q, Lin TH, Der CJ, et al. Integrin -mediated activation of MEK and mitogen-activited protein kinase is independent of Ras. J Biol Chem, 1996, 271: 18122-18127
70. Kapron-Bras C, Fitz-Gibbon L, Jeevaratnam P, et al. Stimulation of tyrosine phosphorylation and accumulation of GTP-bound p21ras upon antibody -mediated alpha 2 beta 1 integrin activation in T-lymphoblastic cells. J Biol Chem, 1993, 268: 20701-20704
71. Ding B, Price RL, Goldsmith EC, et al. Left ventricular hypertrophy in ascending aortic stenosis mice. Circulation, 2000,101:2854-2862
72. Spinale FG, Coker ML, Bond BR, et al. Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target. Cardiovasc Res, 2000, 46:225-238
73. Guo H, Zucker S, Gordon JK, et al. Stimulation of matrix metalloproteinase production by recombinant extracellular matrix metalloproteinase inducer from transfected Chinese hamster ovary cell. J Biol Chem, 1997,272:24-27
74. Lim M, Martinez T, Jablons D, et al. Tumor derived EMMPRIN(extracellular matrix metalloproteinase inducer) stimulates colllagenase transcription through MAPK p38 . FEBS Lett, 1998,441:88-92
75. Nagase H. Activation mechanism of matrix metalloproteinases. Biol Chem, 1997, 378: 151-160
76. Spinale FG, Krombach RS, Coker ML et al. Myocardial matrix inhibition during developing congestive heart failure in pigs, effect on left ventricular geometry and function. Circ Res, 1999, 85: 364-376
77. Li YY, Feng YQ, Kadokami T, et al. Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy. Proc Natl Acad Sci USA, 2000, 97(23): 12746-12751
78. Hoit BD, Takeishi Y, Cox MJ, et al. Remodeling of the left atrium in pacing induced atrial cardiomyopathy. Mol Cell Biochem, 2002,238:145-150
79. Li YY, Feng YQ, Kadokami T, et al. Myocardiol extracellular matrix remodeling in transgenic mice overexpression tumor necrosis factor alpha can be modulated by
anti-tumor necrosis factor alpha therapy. Proc Natl Acad Sci USA 2000, 97: 12746 - 12751
80. Li H, Simon H, Bocan TM, et al. MMP/TIMP expression in spontaneously hypertensive heart failure rats: the effect of ACE-and MMP-inhibition. Cardiovas Res, 2000,46:298-306
81. Thomas CV, Coker ML, Zellner JL, et al. Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation, 1998,97: 1708-1715
82. Coker ML, Zellner JL, Crumbley AJ, et al. Defects in matrix metalloproteinase inhibitory stoichiometry and selective MMP induction in patients with nonischemic or ischemic dilated cardiomyopathy. Ann New York Acad Sci, 1999,878:559-562
83. Rouet-benzineb P, Gontero B, Dreyfus P, et al.Angiotensin II induces nuclear factor- k B, activation in cultured neonatal rat cardiomyocytes through protein kinase C signaling pathway. J Mol Cell Cardiol, 2000,32:1767-1778
84. Bergman MR, Kao RH, McCune SA, et al. Myocardial tumor necrosis factor-alpha secretion in hypertensive and heart failure prone rats. Am Physiol, 1999, 277: H543 -550
85. Bozkurt B, Kribbs SB,Clubb FJ,et al.Pathophysiologically relevant concentration of tumor necrosis factor-promote progressive left ventricular dysfunction and remodeling in rats. Circualtion, 1998,97:1382-1391
86. Brilla CG, Matsubara L, Weber KT. Advanced hypertensive heart disease in spontaneously hypertensive rats. Lisinopril- mediated regression of myocardial fibrosis. Hypersion, 1996,28:269-275
87. Sensaki H, Paolocci N, Gluzband Y, et al. 尾 -blocker prevents sustained metalloproteinase activation and diastolic stiffening induced by angiotensin II combined with evolving cardiac dysfunction. Circ Res, 2000,80:807-818
88. Itoh Y, Tto A, Iwata K, et al. Plasma membrane-band tissue inhibitor of metalloproteinase (TIMP-2) specifically inhibits matrix metalloproteinase 2 (gelatinase A) activated on the cell surface. J Biol Chem, 1998,273:24360-24367
89. Roan EC, Jacobs W, Kin YS, et al. Calcium influx modulates expression of matrix metalloproteinase-2 (72-kDa type IV collagenase, gelatinase A). J Biol Chem, 1994,269:21505-21511
90. Tyagi SC, Kumar S, Katwa L. Differential regulation of extracellular matrix
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4. Ding B, Price RL, Goldsmith EC, et al. Left ventricular hypertrophy in ascending aortic stenosis mice: anoikis and the progression to early failure. Circulation. 2000,101 (24): 2854-2862
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14. Cplan LR, D'Cruz, Hier DB, et al. Atrial size, atrial fibrillation and stroke. Ann Nerol, 1986,19:158-161
15. Goette A, Honeycutt G, Langberg JJ, et al. Electrical remodeling in atrial fibrillation. Time course and mechanisms. Circulation, 1996,94:2968-2974
16. Unverferth DV, Fertel RH, Unverferth B J, et al. Atrial fibrillation in mitrial stenosis: histologic, hymodynamic and metabolic factors. Int J Cardiol, 1984,5:143-154
17. Goette A, Staack T, Rocken C, et al. Increased expression of extracellular signalregulated kinase and angiotensin-coverting enzyme in human atria during atrial fibrillation. J Am Coll Cardiol, 2000,35:1669-1677
18. Shirani J, Alaeddini J. Structure remodeling of the left atrial appendage in patients with chronic non-valvular artial fibrillation: implications for thrombus formation, systemic embolism, and assessment by transesophageal echocardiography. Cardiovasc Pathol, 2000,9:95-101
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20. Bosch RF, Grammer JB, Kuhlkamp V, et al. Electrical remodeling in atrial fibrillation—cellular and molecular mechanisms. Z Kardiol, 2000,89 (9): 795-802
21. Thiedemann KU, Ferrans VJ. Left atrial structure in mitral valcular disease. Am J Pathol, 1977,89:575-604
22. Mary-Rabine L, Albert A, Pham TD, et al. The relationship of human atrial cellular electrophysiology to clinical function and ultrastructure. Cir Res, 1983,52:188-199
23. Aime-Sempe C, Fplliguet T, Rucker-Martin C, et al. Myocardial cell death in fibrillating and dilated human right atria. J Am Coll Cardiol, 1999,34:1577-1586
24. Wouters L, Liu G-S, Flameng W, et al. Structural remodeling of atrial myocardium in patients with cardiac valve disease and atrial fibrillation. Exp Clin Cardiol, 2001, 5: 158-163
25. Schotten U, Ausma J, Stellbrink C, et al. Cellure mechanisms of depressed artial contractility in patients with chronic atrial fibrillation. Circulation, 2001,103:691-698
26. Wouters L, Liu G-S, Flameng W, et al. Structural remodeling of atrial myocardium in patients with cardiac valve disease and atrial fibrillation. Exp Clin Cardiol, 2001,5:158-163
27. Boyden PA, Tilley LP, Pham TD, et al. Effects of left atrial enlargement on atrial transmembrane potentials and structure in dogs with mitral valve fibrosis. Am J Cardiol, 1982,49:1896-1908
28. Frustaci A, Chimenti C, Bellocci F, et al. Histological substrate of attrial biopsies in patients with lone atrial fibrillation. Circulation, 1997,96:1180-1184
29. Brundel BJM, Ausma J, van Gelder IC, et al. Calpain activity is related to ion-channel, structural and electrical remodeling in human paroxymal and persistent atrial fibrillation. Thesis. University of Groningen, Groningen, 2000
30. Ausma J, Wijffels M, Thone F, et al. Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation, 1997, 96:3157-3163
31. Leistad E, Aksnes G, Verbug E, et al. Atrial contractile dysfunction after short-term atrial fibrillation is reduced by verapamile but increased by BAY K8644. Circulation, 1996,93(9): 1747-1754
32. Pirolo JS, Hutchins GM, Moore GW. Myocyte vacuolization in infarct border zones is reversible. Am J Pathol, 1985,121: 444-450
33. Borg TK, Rubin K, Lundgren E, et al. Recognition of extracellular matrix components by neonatal and adult cardiac myocytes. Dev Biol, 1984,104:86-96
34. Mary-Rabine L, Albert A, Pham TD,et al.The relationship of human atrial cellular electrophysiology to clinical function and ultrastructure. Cir Res, 1983, 52: 188 - 199
35. Thijssen V, Ausma J, Borgers M. Structural remodeling during chronic atrial fibrillation: act of programmed cell survival. Cardiovasc Res, 2001,52:14-24
36. White CW, Jerver RE, Weiss HR,et al.The effect of atrial fibrillation on atrial pressure-volume and flow relationship. Circ Res,1982, 51:205-215
37. Van Wagoner DR, Pond AL, Lamorgese M, et al. Atrial L-type Ca2+ currents and human atrial fibrillation. Circ Res, 1999, 85(5): 428-36
38. Ausma J, Dispersyn GD, Duimel H, et al. Changes in ultrastructrual calcium distribution in goat atria during atrial fibrillation. J Mol Cell Cardiol, 2000, 32: 355 -364
39. Goette A, Staack T, Rocken C, et al. Increased expression of extracellular signal-regulated kinase and angiotensin -converting enzyme in human atria during atrial fibrillation. J Am Coll Cardiol, 2000:35:1669-1677
40. Goette A, Arndt M, Rocken C, et al. Regulation of angiotensin II receptor subtypes during atrial fibrillation in humans. Circulation, 2000,101:2678-2781
41. Rogg H, de Gasparo M, Graedel E, et al. Angiotensin II-receptor subtypes in human atria and evidence for alterations in patients with cardiac function. Eur Heart J, 1996,17:1112-1120
42. Asno K, Dutcher DL, Port JD, et al.Selective downregulation of the angiotensin II AT1-R receptor subtype in failing human ventricular myocardium. Circulation, 1997, 95:1193-1200
43. Matsubara H.Pathophysiological role of angiotensin II type receptor in cardiovascular and renal diseases. Circ Res,1998, 83:1182-1191
44. Robinson TF, Cohen-Gould L, Factor SM, et al. Structure and function of connective tissue in cardiac muscle: collagen types I and III in endomysial struts and pericellular fibers. Scanning Microsc, 1988, 2(2): 1005-1015.
45. Boixel C, Fontaine V, Rucker-Marin C, et al. Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat. J Am Coll Cardiol, 2003,42:336-344
46. Kuwahara F, Kai H, Tokuda K, et al. Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure- overloaded rats. Circulation, 2002, 106(1): 130-135.
47. Lijnen P, Petrov V. Antagonism of the renin-angiotensin-aldosterone system and collagen metabolism in cardiac fibroblasts. Methods Find Exp Clin Pharmacol. 1999, 21(3): 215-27
48. Ramires FJ, Sun Y, Weber KT. Myocardial fibrosis associated with aldosterone or angiotensin II administration: attenuation by calcium channel blockade. J Mol Cell Cardiol, 1998,30(3): 475-483
49. Tharaux PL, Chatxiantoniou C, Fakhouri F et al. Angiotensin II activates collagen I gene through a mechanism involving the MAP/ER kinase pathway. Hypertension, 2000,36,330-336
50. Varo N, Iraburu MJ, Varela M, et al. Chronic AT(1) blockade stimulates extracellular collagen type I degradation and reverses myocardial fibrosis in spontaneously hypertensive rats. Hypertension,2000, 35(6): 1197-1202.
51. Gampbell SE, Katwa LC. Angiotensin II stimulated expression of transforming growth factor beta-1 in cardiac fibroblasts and myofibroblasts. J Med Cell Cardiol, 1997,29(7): 1947-1958
52. Horiuchi M, Akishita M, Dxau VJ. Recent progress in angiotensin II type 2 receptor research in the cardiovascular system. Hypertension, 1999,33:613-621
53. Senbonmatsu T, Ichihara S, Price E Jr, et al. Evidence for angiotensin II type 2 receptor -mediated cardiac myocyte enlargement during in vivo pressure overload. J Clin Invest, 2000,106(3): R25-R29
54. Yamada H, Horiuchi M, Akishita M, et al. Regulation of vascular develoment and differentiation by angiotensin II type 2 receptor. Hypertension, 1997,30:470-475
55. Yamada T, Akishita M, Pollman M, et al. Angiotensin II type 2 receptor mediates vascular smooth muscle cell apoptosis and antagomize angiotensin type 1 receptor action: an in vitro gene transfer study. Life Sci, 1998,63:PL289-PL295
56. Dimmeler S, Rippmann V, Weiland U, et al. Angiotensin II induces apoptosis of human endothelial cells: protective effect of nitric oxide. Circ Res, 1997,81:970-976
57. Tsutsumi Y, Mataubara H, Ohkubo N, et al. Angiotensin II type 2 receptor is upregulated in human heart with interstitial fibrosia and cardiac fibroblasts are the major cell type for its expression. Circ Res, 1998,1035-1046
58. Siwik DA, Pagano PJ, Colucci WS. Oxidative stress regulates collagen synthesis and matrix matelloproteinase activity in cardiac fibroblasts. Am J Physiol (Cell Physiol), 2001,280(1): C53-C60
59. Kumaran C, Shivakumar K. Superoxide-mediated activation of cardiac fibroblasts by serum factors in hypomagnesemia. Free Radic Biol Med, 2001,31(7): 882-886
60. Li PF, Diez R, von Harsdorf R, et al. Superoxide induces apoptosis in cardiomyocytes, but proliferation and expression of transforming growth factor beta in cardiac fibroblast. FFBB-Lett, 1999,488:206-210
61. Korantzopoulos P, kolettis T, Siogas K, et al. Atrial fibrillation and eletrical remodeling: the role of inflammation and oxidative stress. Med Sci Moint, 2003, 9:RA225-229
62. Hsueh WA, Law RE, Do YS. Integrins, adhesion, and cardiac remodeling. Hypertension, 1998,31[1 part 2]: 176-180
63. Collo G, Srarr L, Quaranta V. A new isoform of the laminin receptor integrin alpha 7 betal is developmentally regulated in skeletal muscle. J Biol Chem, 1993, 268: 19019-19024
64. Fassler R, Rohwedel J, Malsterv V, et al. Differentiation and integrity of cardiac muscle cells are impaired in the absence of 尾 , integrin. J Cell Scien, 1996, 109:2989-2999
65. Lewis JM, Schwartz MA. Mapping in vivo associations of cytoplasmic proteins with integrin beta 1 cytoplasmic domain mutants. Mol Biol Cell, 1995,6:151-160
66. Arndt M, Lendeckel U, Rocken C, et al. Altered expression of ADAMs(A Disintegrin And Metalloproteinase) in fibrillation human atria. Circulation, 2002,105:720-725
67. Werb Z, Yan Y. A cellular striptease act. Science, 1998,282:1279-1280
68. Pechon J, Slack JL, Reddy P, et al. An essential role for ectodomain shedding in mammalian development. Science, 1998,282:1281-1284
69. Chen Q, Lin TH, Der CJ, et al. Integrin -mediated activation of MEK and mitogen-activited protein kinase is independent of Ras. J Biol Chem, 1996, 271: 18122-18127
70. Kapron-Bras C, Fitz-Gibbon L, Jeevaratnam P, et al. Stimulation of tyrosine phosphorylation and accumulation of GTP-bound p21ras upon antibody -mediated alpha 2 beta 1 integrin activation in T-lymphoblastic cells. J Biol Chem, 1993, 268: 20701-20704
71. Ding B, Price RL, Goldsmith EC, et al. Left ventricular hypertrophy in ascending aortic stenosis mice. Circulation, 2000,101:2854-2862
72. Spinale FG, Coker ML, Bond BR, et al. Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target. Cardiovasc Res, 2000, 46:225-238
73. Guo H, Zucker S, Gordon JK, et al. Stimulation of matrix metalloproteinase production by recombinant extracellular matrix metalloproteinase inducer from transfected Chinese hamster ovary cell. J Biol Chem, 1997,272:24-27
74. Lim M, Martinez T, Jablons D, et al. Tumor derived EMMPRIN(extracellular matrix metalloproteinase inducer) stimulates colllagenase transcription through MAPK p38 . FEBS Lett, 1998,441:88-92
75. Nagase H. Activation mechanism of matrix metalloproteinases. Biol Chem, 1997, 378: 151-160
76. Spinale FG, Krombach RS, Coker ML et al. Myocardial matrix inhibition during developing congestive heart failure in pigs, effect on left ventricular geometry and function. Circ Res, 1999, 85: 364-376
77. Li YY, Feng YQ, Kadokami T, et al. Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy. Proc Natl Acad Sci USA, 2000, 97(23): 12746-12751
78. Hoit BD, Takeishi Y, Cox MJ, et al. Remodeling of the left atrium in pacing induced atrial cardiomyopathy. Mol Cell Biochem, 2002,238:145-150
79. Li YY, Feng YQ, Kadokami T, et al. Myocardiol extracellular matrix remodeling in transgenic mice overexpression tumor necrosis factor alpha can be modulated by
anti-tumor necrosis factor alpha therapy. Proc Natl Acad Sci USA 2000, 97: 12746 - 12751
80. Li H, Simon H, Bocan TM, et al. MMP/TIMP expression in spontaneously hypertensive heart failure rats: the effect of ACE-and MMP-inhibition. Cardiovas Res, 2000,46:298-306
81. Thomas CV, Coker ML, Zellner JL, et al. Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation, 1998,97: 1708-1715
82. Coker ML, Zellner JL, Crumbley AJ, et al. Defects in matrix metalloproteinase inhibitory stoichiometry and selective MMP induction in patients with nonischemic or ischemic dilated cardiomyopathy. Ann New York Acad Sci, 1999,878:559-562
83. Rouet-benzineb P, Gontero B, Dreyfus P, et al.Angiotensin II induces nuclear factor- k B, activation in cultured neonatal rat cardiomyocytes through protein kinase C signaling pathway. J Mol Cell Cardiol, 2000,32:1767-1778
84. Bergman MR, Kao RH, McCune SA, et al. Myocardial tumor necrosis factor-alpha secretion in hypertensive and heart failure prone rats. Am Physiol, 1999, 277: H543 -550
85. Bozkurt B, Kribbs SB,Clubb FJ,et al.Pathophysiologically relevant concentration of tumor necrosis factor-promote progressive left ventricular dysfunction and remodeling in rats. Circualtion, 1998,97:1382-1391
86. Brilla CG, Matsubara L, Weber KT. Advanced hypertensive heart disease in spontaneously hypertensive rats. Lisinopril- mediated regression of myocardial fibrosis. Hypersion, 1996,28:269-275
87. Sensaki H, Paolocci N, Gluzband Y, et al. 尾 -blocker prevents sustained metalloproteinase activation and diastolic stiffening induced by angiotensin II combined with evolving cardiac dysfunction. Circ Res, 2000,80:807-818
88. Itoh Y, Tto A, Iwata K, et al. Plasma membrane-band tissue inhibitor of metalloproteinase (TIMP-2) specifically inhibits matrix metalloproteinase 2 (gelatinase A) activated on the cell surface. J Biol Chem, 1998,273:24360-24367
89. Roan EC, Jacobs W, Kin YS, et al. Calcium influx modulates expression of matrix metalloproteinase-2 (72-kDa type IV collagenase, gelatinase A). J Biol Chem, 1994,269:21505-21511
90. Tyagi SC, Kumar S, Katwa L. Differential regulation of extracellular matrix