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、心律失常和纤维化的原因。在人类中，Ang-(-12)（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。进一步证明，从接受心脏手术以控制心房颤动 (AF) 的患者获得的心房肌细胞中，Ang-(1-12) 大量表达，并且相关的发现是，在人和人体内，心肌糜酶将 Ang-(1-12) 转化为 Ang II心房和左心室肌细胞产生这样的假设：拉伸相关的心肌食糜酶表达增加以及 Ang-(1-12) 转化为 Ang II 通过激活基质促进 AF 的发生金属蛋白酶 (MMP) 和连接蛋白 (Cx) 的破坏，间隙连接蛋白对细胞间通讯和电稳定性很重要。目标 1 将检验激活的假设 与拒绝移植的心脏的正常左心房相比，因二尖瓣反流 (MR) 进行瓣膜修复的患者的左心房组织中，食糜酶有助于升高 Ang-(1-12)/Ang II/MMP-9 轴和间隙连接重塑；目标 2 将显示在体外循环之前以及 4、12、24 和 48 小时时间点获得的心包液中评估的心房组织表达和食糜酶 Ang-(1-12)/Ang II/MMP-9 成分的释放是如何变化的与 a) 电影磁共振成像的心房重塑和功能以及手术前后进行的 3 维分析有关，b) 术后 AF 的发生。在目标 3 中，将检验以下假设：心房肌细胞的拉伸和/或缺氧复氧会增加繁殖人类心房肌细胞的 HL1 细胞的食糜酶和 Cx 破坏以及电不稳定性。这些目标的实现将为测试食糜酶抑制在治疗/预防 AF 中的功效的临床试验提供动力。