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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(申请人提供)：醛固酮与心肌重塑和衰竭的过程有关。醛固酮可能通过多种机制调节炎症、心肌细胞收缩和松弛、氧化应激和间质基质，从而影响心肌表型。在体外研究中，醛固酮可诱导心肌细胞凋亡、p67Phox和促炎信号介质如NOS2。这些观察结果使我们假设，在血流动力学超负荷和增加的醛固酮系统刺激下，醛固酮介导了心肌细胞的表型反应。过氧化物酶体增殖物激活受体(PPAR)信号转导通路虽然是能量控制的调节者，但可以减轻心肌肥厚、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。我们将通过在小鼠体内和体外在心肌细胞和成纤维细胞中操纵醛固酮水平，以及它们与PPAR在分子、细胞和器官水平上调节结构和功能重建的相互作用来探索这些途径。在目标1中，我们将测试醛固酮和PPAR在调节压力超负荷心脏重构中的作用。我们将验证PPAR抑制醛固酮诱导的不良心脏重塑的假设。我们将使用压力超负荷的小鼠和慢性醛固酮输注。我们将使用合成的PPAR激动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PPARα缺失小鼠心肌慢性炎症或氧化应激的进展来介导重构。在目标2中，我们将测试醛固酮在诱导心肌重构中肥大/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途径以及b)氧化应激诱导心肌表型的机制。在目标3中，我们将测试醛固酮在调节异常的心肌细胞收缩表型中的作用。我们将验证这一假设，即醛固酮对心肌细胞收缩表型既有急性影响，也有慢性影响。在体外，成年大鼠和小鼠心肌细胞在短期(分钟)或长期(小时)暴露于外源性醛固酮后，将同时测量心肌细胞的收缩/松弛和细胞内钙瞬变。这些研究将提供对压力超负荷心脏中的醛固酮信号机制的新理解，并将与患者心力衰竭的常见原因直接相关。