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Role of Aldosterone in Cardiac Remodeling

醛固酮在心脏重塑中的作用

基本信息

批准号：
7841118
负责人：
Flora Sam
金额：
$ 28.23万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7841118
关键词：
Acute Adult Affect Agonist Aldosterone Apoptosis Apoptotic Attenuated Calcium Cardiac Cardiac Myocytes Cells Cessation of life Chronic Echocardiography Epidermal Growth Factor Receptor Exposure to Failure Fenofibrate Fibroblasts Gene Proteins Heart Heart Hypertrophy Heart failure Hour Hypertension Hypertrophy In Vitro Inflammation Inflammatory Inflammatory Response Infusion procedures Knockout Mice Lead Left Left Ventricular Remodeling Ligands MAP Kinase Gene Measurement Measures Mechanics Mediating Mediator of activation protein Modeling Molecular Mus Muscle Cells Myocardial Myocardial Infarction Myocardium NADP NADPH Oxidase NOS2A gene Organ Oxidative Stress Oxidative Stress Pathway PPAR alpha Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Phenotype Physiologic intraventricular pressure Process Rattus Receptor Signaling Relaxation Renin-Angiotensin-Aldosterone System Research Personnel Rodent Role Signal Transduction Sodium Chloride Structure System Techniques Testing Transgenic Mice Ventricular Ventricular Remodeling Water aorta constriction ascending aorta base hemodynamics improved in vivo interstitial mortality mouse model neutrophil cytosol factor 67K non-genomic pressure programs protein expression research study response troglitazone

项目摘要

DESCRIPTION (provided by applicant): Aldosterone is implicated in the process of myocardial remodeling and failure . Aldosterone may affect myocardial phenotype by regulating inflammation, myocyte contraction and relaxation, oxidative stress, and the interstitial matrix through a variety of mechanisms. In in vitro studies, aldosterone induces myocyte apoptosis, p67 phox and pro-inflammatory signal mediators such as NOS2. These observations lead us to the hypothesis that aldosterone mediates the phenotypic responses of myocardial cells in hemodynamic overload and increased aldosterone system stimulation . Peroxisome proliferator-activated receptor (PPAR) signaling , although regulators of energy control, attenuate cardiac hypertrophy, oxidative stress and apoptosis and may improve myocardial remodeling through pathways such as inflammation . We will explore these pathways by manipulating aldosterone levels, in vivo in mice and in vitro in cardiac myocytes and fibroblasts and their interaction with PPARs in mediating structural and functional remodeling at the molecular, cellular and organ levels. In Aim 1 we will test the role of aldosterone and PPARs in mediating pressure overload cardiac remodeling . We will test the hypothesis that PPARs inhibit aldosterone-induced adverse cardiac remodeling. We will use mice with pressure overload and chroni c aldosterone infusions . We will use synthetic PPAR activators, fenofibrate and troglitazone, to determine if cardiac remodeling is inhibite d and further test if aldosterone mediates remodeling via progression of chronic inflammation or oxidative stress in the myocardium of PPARalpha null mice. In Aim 2 we will test the role of aldosterone in inducing a hypertrophic/proliferative and apoptotic phenotype in myocardial remodeling . In in vivo experiments, we will test the mechanism whereby aldosterone induces a myocardial phenotype via a) the EGFR and MAPK pathway; and b) oxidative stress. In Aim 3 we will test the role of aldosterone in mediating an abnormal myocyte contractile phenotype. We will test the hypothesis that aldosterone exerts both acute and chronic effects on myocyte contractile phenotype. Myocyte contraction/relaxation and intracellular calcium transients will be measured simultaneously in adult rat and mouse myocytes following short (min ) or long (hrs) term exposure to exogenous aldosterone in vitro. These studies will provide new understanding of the mechanisms of aldosterone signaling in the pressure overload heart and will have direct relevance to a common cause of heart failure in patients.

描述（由申请人提供）：醛固酮参与心肌重构和衰竭的过程。醛固酮可能通过多种机制调节炎症、心肌细胞收缩和舒张、氧化应激和间质基质，从而影响心肌表型。在体外研究中，醛固酮可诱导肌细胞凋亡、p67 phox和促炎信号介质如NOS2。这些观察结果导致我们假设醛固酮介导心肌细胞在血流动力学过载和醛固酮系统刺激增加时的表型反应。过氧化物酶体增殖物激活受体（PPAR）信号，虽然调节能量控制，减轻心脏肥大，氧化应激和细胞凋亡，并可能通过炎症等途径改善心肌重塑。我们将通过控制体内小鼠和体外心肌细胞和成纤维细胞的醛固酮水平，以及它们与ppar在分子、细胞和器官水平上介导结构和功能重塑的相互作用来探索这些途径。在目的1中，我们将测试醛固酮和ppar在介导压力过载心脏重构中的作用。我们将验证ppar抑制醛固酮诱导的不良心脏重构的假设。我们将使用压力过载和慢性醛固酮输注的小鼠。我们将使用合成的PPAR激活剂非诺贝特和曲格列酮来确定心脏重构是否受到抑制，并进一步测试醛固酮是否通过PPAR α缺失小鼠心肌慢性炎症或氧化应激的进展介导重构。在目的2中，我们将测试醛固酮在心肌重构中诱导肥厚/增殖和凋亡表型中的作用。在体内实验中，我们将测试醛固酮通过a) EGFR和MAPK途径诱导心肌表型的机制；b)氧化应激。在Aim 3中，我们将测试醛固酮在介导异常肌细胞收缩表型中的作用。我们将测试醛固酮对肌细胞收缩表型的急性和慢性影响的假设。在体外短期（min）或长期（hrs）暴露于外源性醛固酮后，将同时测量成年大鼠和小鼠肌细胞的肌细胞收缩/舒张和细胞内钙瞬变。这些研究将为压力过载心脏中醛固酮信号传导的机制提供新的理解，并将与患者心力衰竭的常见原因直接相关。