The Chymase Angiotensin-(1-12) Axis in Heart Disease

描述（由申请人提供）： 在心脏中，细胞内或间质形成的Ang II活性增加是心脏重塑、心律失常和纤维化的原因。在人类中，Ang-（-12）是Ang I的延伸形式，负责心肌细胞中Ang II的非肾素依赖性合成。进一步证实了心房肌细胞中大量的Ang-（1-12）表达，这些心房肌细胞是从接受心脏手术以控制心房颤动（AF）的患者中获得的，并且相关的发现是在人心房和左心室肌细胞中心脏糜酶将Ang-（1-12）转化为Ang II，这产生了牵张相关的心脏糜酶表达增加和Ang-（1-12）表达增加的假设。转化为Ang II通过激活基质金属蛋白酶（MMP）和破坏连接蛋白（Cx）（在细胞-细胞通讯和电稳定性中重要的间隙连接蛋白）促进AF的发生。目标1将检验激活 糜酶有助于升高的Ang-（1-12）/Ang II/MMP-9轴和来自经历二尖瓣反流（MR）的瓣膜修复的患者的左心房组织中的间隙连接重构，相对于来自移植排斥的心脏的正常左心房;目的2将显示心房组织中糜酶Ang-（1-12）/Ang II/MMP-9组分的表达和释放，在心肺转流术前和4、12、24和48小时时间点获得的心包液中进行评估，与a）手术前后进行的电影磁共振成像三维分析的心房重构和功能相关，以及B）术后房颤的发生率。在目的3中，将检验心房肌细胞的牵张和/或缺氧-复氧增加复制人心房肌细胞的HL 1细胞中的糜蛋白酶和Cx破坏和电不稳定性的假设。这些目标的实现将为测试糜酶抑制剂在治疗/预防AF中的功效的临床试验提供动力。

DESCRIPTION (provided by applicant): In the heart, increased Ang II activity from intracellular or interstitial formation is a cause of cardiac remodeling, arrhythmias, and fibrosis. In humans, Ang-(-12), an extended form of Ang I, accounts for nonrenin dependent synthesis of Ang II in cardiac myocytes. Further demonstration of substantial Ang-(1-12) expression in atrial myocytes obtained from patients undergoing cardiac surgery for control of atrial fibrillation (AF) and the associated discovery that cardiac chymase converted Ang-(1-12) into Ang II in both human atrial and left ventricular myocytes generates the hypothesis that stretch-related increased cardiac chymase expression and Ang- (1-12) conversion to Ang II promotes the occurrence of AF through activation of matrix metalloproteinases (MMP) and disruption of connexins (Cx), gap junctions proteins important in cell-cell communication and electrical stability. Aim 1 will test the hypothesis that activation of chymase contributes to elevated Ang-(1-12)/Ang II/MMP-9 axis and gap junction remodeling in left atrial tissue from patients undergoing valve repair for mitral valve regurgitation (MR) vs. normal left atria from hearts rejected for transplantation; Aim 2 will show how atrial tissue expression and release of chymase Ang-(1-12)/Ang II/MMP-9 components, assessed in pericardial fluid obtained before cardiopulmonary bypass and at 4, 12, 24 and 48 hour time points, are related to a) atrial remodeling and function from cine-magnetic resonance imaging with 3-dimensional analysis performed before and after surgery and b) the occurrence of AF postsurgery. And in Aim 3 will test the hypothesis that stretch and/or hypoxia-reoxygenation of atrial myocytes increases chymase and Cx disruption and electrical instability in HL1 cells which reproduce human atrial myocytes. Achievement of these aims will provide impetus for a clinical trial testing the efficacy of chymase inhibition in the treatment/prevention of AF.