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

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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.