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

心脏病中的食糜酶血管紧张素 (1-12) 轴

• 批准号: 8811838
• 负责人: Louis J. Dell'Italia
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811838
• 关键词: 9 year old; Accounting; Achievement; Acute; Affect; American; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Anti-Arrhythmia Agents; Arrhythmia; Atrial Fibrillation; Cardiac; Cardiac Myocytes; Cardiac Surgery procedures; Cardiopulmonary Bypass; Caring; Cause of Death; Cell Communication; Cells; Cessation of life; Chymase; Cine Magnetic Resonance Imaging; Clinical Trials; Confocal Microscopy; Connexins; Data; EFRAC; Failure; Fibrosis; Functional disorder; Gap Junctions; Gelatinase B; Heart; Heart Atrium; Heart Diseases; Hour; Human; Hydrolysis; Hypertension; Hypoxia; Immunohistochemistry; In Vitro; Incidence; Ischemia; Left; Left atrial structure; Liquid substance; Location; Magnetic Resonance Imaging; Matrix Metalloproteinases; Measurement; Mediating; Medical; Metabolism; Mitral Valve; Mitral Valve Insufficiency; Monitor; Muscle Cells; Operative Surgical Procedures; Pathway interactions; Patients; Pericardial body location; Pharmaceutical Preparations; Postoperative Period; Prevention; Procedures; Relative (related person); Renin; Reperfusion Injury; Reperfusion Therapy; Research; Rodent; Stretching; Stroke; System; Testing; Three-dimensional analysis; Time; Tissues; Transplantation; United States; Ventricular; Veterans; base; connexin 40; efficacy testing; heart function; high risk; inhibitor/antagonist; insight; interstitial; mast cell; matrix metalloproteinase 12; meetings; novel strategies; pericardial sac; public health relevance; receptor; repaired; success

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.

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，心律不齐和纤维化的原因。在人类中，Ang - （-12），ANG I的扩展形式，占心肌细胞中ANG II的依赖性合成。 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通过激活基质金属蛋白酶（MMP）的激活和连接蛋白（CX）的破坏，间隙连接蛋白在细胞细胞通信和电稳定性中很重要的情况。 AIM 1将检验激活的假设 Chymase有助于升高（1-12）/ANG II/MMP-9轴和左心房组织中的间隙连接重塑，该患者正在接受瓣膜瓣瓣浮肿（MR）的瓣膜修复患者（MR）与正常左心房的心脏拒绝接受移植的心脏。 AIM 2将显示在心肺旁路之前获得的心包液和4、12、24和48小时时间点的心包液中评估的Chymase Ang-（1-12）/ANG II/MMP-9成分的chymase Ang-（1-12）/ANG II/MMP-9组件如何与A）相关的a）与a）与a）相关的术语进行了3 d-dimenance Imation Image and trimention and and and offer的chymase Ang-（1-12）/Ang II/MMP-9成分。 AF术后。在AIM 3中，将检验以下假设：心肌细胞的伸展和/或缺氧 - 胜蛋白会增加Chymase和Cx的破坏和HL1细胞中繁殖人心房心肌细胞的电不稳定性。这些目标的实现将为临床试验提供动力，该试验测试Chymase抑制在治疗/预防AF中的功效。