Modulation of Natriuretic Peptides via Caveolin in Hypertrophy and Heart Failure.

通过 Caveolin 对肥大和心力衰竭中利尿钠肽的调节。

• 批准号: 8196337
• 负责人: DAVID M ROTH
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196337
• 关键词: Address; Adrenergic Agonists; Affect; American; Animal Model; Atrial Natriuretic Factor; Binding; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Caveolae; Caveolins; Cell Surface Receptors; Cell physiology; Chronic; Clinical Trials; Complex; Congestive Heart Failure; Coupled; Data; Death Certificates; Development; Diagnosis; Diuretics; Endothelin-1; Family suidae; Gene Expression; Gene Transfer; Genes; Healthcare Systems; Heart Atrium; Heart Hypertrophy; Heart failure; Hypertension; Hypertrophy; Knock-out; Left; Left ventricular structure; Lipids; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Myocardial Ischemia; Myocardium; Natriuretic Peptides; Nuclear; Patient Care; Patients; Phenotype; Physiologic intraventricular pressure; Physiological; Pre-Clinical Model; Property; Protein Isoforms; Public Health; Quality of life; Receptor Signaling; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Stimulus; Structural Protein; Techniques; United States; Ventricular; Work; abstracting; base; caveolin-3; cell growth; clinically relevant; design; effective therapy; mortality; new therapeutic target; novel therapeutics; nuclear factor 1; overexpression; pre-clinical; pressure; programs; public health relevance; saluretic

DESCRIPTION (provided by applicant): Project Summary/Abstract Cardiac hypertrophy is a critical determinant of cardiac remodeling and the progression of heart failure. Heart failure remains a major public health problem and effective therapies are limited. Molecular signaling involved in cardiac hypertrophy is complex and involves a number of cell surface receptors, signal transduction pathways and nuclear factors. An emerging theme in signal transduction is the concept of microdomains that contain cell surface receptors and intracellular signaling molecules and provide order to signaling pathways. Caveolae are specialized microdomains containing the structural proteins, caveolins that bind, organize and regulate receptors and signaling molecules involved in numerous cell functions including cell growth and hypertrophy. Knocking out the gene for the muscle specific isoform of caveolin (Caveolin-3, Cav-3) results in cardiac hypertrophy and cardiomyopathy. Conversely, overexpression of Cav-3 in cardiac myocytes blocks adrenergic agonist and endothelin-1 induced myocyte hypertrophy. Thus, loss of Cav-3 is sufficient to induce a molecular program resulting in cardiac hypertrophy and cardiomyopathy and overexpression of Cav-3 may be a means to negatively regulate cardiac hypertrophy. Atrial natriuretic peptide (ANP) has diuretic, natriuretic, and vasodilatory properties that inhibit cardiac hypertrophy. A relationship between ANP, caveolae and caveolins was proposed nearly two decades ago. ANP is present within caveolae, closely associated with Cav-3 and may be secreted via caveolae from cardiac myocytes. The preliminary data show that cardiac myocyte-specific overexpression of Cav-3 produces a cardiac phenotype with dramatically increased expression of ANP in the left ventricle at baseline and a reduction in cardiac hypertrophy, increased survival and preserved cardiac function in the face of left ventricular pressure overload. The proposal is designed to address the hypothesis that Cav-3 modulates ANP expression to reduce cardiac hypertrophy and heart failure and to evaluate overexpression of Cav-3 as a unique and beneficial means to modulate ANP expression and treat heart failure patients. The following aims will be pursued: Aim 1: Will determine mechanisms for Cav-3 modulation of ANP and ANP coupled signaling in cardiac hypertrophy and heart failure. Aim 2: Will determine if conditional cardiac myocyte-specific overexpression of Cav-3 modulates ANP and ameliorates heart failure induced by pressure overload. Aim 3: Will determine if gene transfer of Cav-3 modulates ANP and shows efficacy in a preclinical model of heart failure in swine. State of the art molecular and physiological techniques will be used in the studies in clinically relevant models of hypertrophy and heart failure in large and small animal models to focus on mechanism and produce important preclinical data to support potential clinical trials on caveolins as novel therapeutics for heart failure patients. PUBLIC HEALTH RELEVANCE: Project Narrative Prevalent cardiovascular diseases such as chronic hypertension and ischemic heart disease result in cardiac hypertrophy and the development of congestive heart failure. Heart failure is associated with high mortality and morbidity and poor quality of life. Heart failure affects nearly 5 million Americans and is listed on 1 out of every 8 death-certificates in the United States. Heart failure is a primary focus of the VA quality enhancement research initiative (QUERI) and remains the number one discharge diagnosis in the VA healthcare system. The work described in this proposal focuses on elucidating mechanisms to support the use of caveolin proteins as novel therapeutic targets for heart failure patients and is of relevance to the VA patient care mission.

描述（由申请人提供）： 项目摘要/摘要心脏肥大是心脏重塑和心力衰竭进展的关键决定因素。心力衰竭仍然是一个主要的公共卫生问题，有效的治疗方法有限。心脏肥大涉及的分子信号传导非常复杂，涉及许多细胞表面受体、信号转导途径和核因子。信号转导中的一个新兴主题是微域的概念，它包含细胞表面受体和细胞内信号分子，并为信号传导途径提供秩序。小凹是一种特殊的微结构域，含有结构蛋白、结合、组织和调节受体的小凹蛋白以及参与细胞生长和肥大等多种细胞功能的信号分子。敲除肌肉特异性小窝蛋白亚型（Caveolin-3、Cav-3）的基因会导致心脏肥大和心肌病。相反，心肌细胞中 Cav-3 的过度表达会阻止肾上腺素能激动剂和内皮素-1 诱导的心肌细胞肥大。因此，Cav-3的缺失足以诱导导致心脏肥大和心肌病的分子程序，并且Cav-3的过度表达可能是负调节心脏肥大的一种手段。心房钠尿肽 (ANP) 具有利尿、利尿钠和血管舒张特性，可抑制心脏肥大。近二十年前就提出了 ANP、小凹和小凹之间的关系。 ANP 存在于小窝内，与 Cav-3 密切相关，并且可能通过小窝从心肌细胞分泌。初步数据表明，心肌细胞特异性过度表达 Cav-3 会产生一种心脏表型，在基线时左心室 ANP 表达显着增加，并且在面对左心室压力时，心脏肥大减少，存活率增加并保留心脏功能超载。该提案旨在解决 Cav-3 调节 ANP 表达以减少心脏肥大和心力衰竭的假设，并评估 Cav-3 的过度表达作为调节 ANP 表达和治疗心力衰竭患者的独特且有益的手段。将追求以下目标： 目标 1：将确定心脏肥大和心力衰竭中 ANP 和 ANP 偶联信号传导的 Cav-3 调节机制。目标 2：确定条件性心肌细胞特异性的 Cav-3 过度表达是否会调节 ANP 并改​​善压力超负荷引起的心力衰竭。目标 3：将确定 Cav-3 的基因转移是否调节 ANP 并在猪心力衰竭的临床前模型中显示出功效。最先进的分子和生理学技术将用于大型和小型动物模型中肥厚和心力衰竭临床相关模型的研究，重点关注机制并产生重要的临床前数据，以支持小窝蛋白作为心脏新疗法的潜在临床试验失败患者。 公共卫生相关性： 项目叙述 慢性高血压和缺血性心脏病等流行的心血管疾病会导致心脏肥大和充血性心力衰竭的发展。心力衰竭与高死亡率和发病率以及低生活质量相关。心力衰竭影响着近 500 万美国人，在美国每 8 份死亡证明中就有 1 人患有心力衰竭。心力衰竭是 VA 质量增强研究计划 (QUERI) 的主要关注点，并且仍然是 VA 医疗系统中排名第一的出院诊断。该提案中描述的工作重点是阐明支持使用小窝蛋白作为心力衰竭患者新治疗靶点的机制，并且与 VA 患者护理任务相关。