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: 8967205
• 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/8967205
• 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; Health; Heart; Heart Atrium; Heart Diseases; Hour; Human; Hydrolysis; Hypertension; Hypoxia; Immunohistochemistry; In Vitro; Incidence; Ischemia; Left; Left atrial structure; Liquid substance; Location; MME gene; 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; 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; meetings; novel strategies; pericardial sac; 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活性增加是心脏重构、心律失常和纤维化的原因。在人类中，Ang-(-12)是Ang I的扩展形式，解释了心肌细胞中Ang II的非肾素依赖性合成。进一步的证据表明，为控制心房颤动(AF)而接受心脏手术的患者的心房肌细胞中有大量Ang-(1-12)的表达，以及相关的发现，在人的心房和左室肌细胞中，心脏糜酶将Ang-(1-12)转化为Ang II，从而产生了一种假说，即牵张相关的心脏糜酶表达增加，Ang-(1-12)转化为Ang II，其机制是通过激活基质金属蛋白酶(MMP)和破坏缝隙连接蛋白(Cx)来促进房颤的发生，缝隙连接蛋白在细胞间通信和电子稳定性中至关重要。目标1将检验这样一个假设，即激活 凝乳酶参与二尖瓣返流(MR)瓣膜修补术患者左心房Ang-(1-12)/Ang II/MMP9轴升高和缝隙连接重构；目的研究体外循环前、术后4、12、24、48h心包液中Chymase Ang-(1-12)/Ang II/MMP9的表达和释放与房颤发生的关系。在目标3中，将检验这样一种假设，即心房肌细胞的拉伸和/或缺氧-复氧增加了复制人心房肌细胞的HL1细胞的糜酶和Cx的破坏和电不稳定性。这些目标的实现将为检验糜酶抑制在治疗/预防房颤中的有效性的临床试验提供动力。