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）： 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。心肌肥大的分子信号转导是一个复杂的过程，涉及许多细胞表面受体、信号转导通路和核因子。信号转导中的一个新兴主题是微区的概念，微区包含细胞表面受体和细胞内信号分子，并为信号通路提供秩序。小窝是一种特殊的微结构域，含有结构蛋白，小窝蛋白结合，组织和调节受体和信号分子，参与许多细胞功能，包括细胞生长和肥大。敲除肌肉特异性小窝蛋白同种型（Caveolin-3，Cav-3）的基因导致心脏肥大和心肌病。相反，Cav-3在心肌细胞中的过表达阻断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，Cav-3的过表达可能是负调节心脏肥大的手段。心房利钠肽（ANP）具有利尿、利钠和舒张血管的特性，可抑制心脏肥大。近二十年前提出了ANP、小窝和小窝蛋白之间的关系。ANP存在于Caveolae内，与Cav-3密切相关，并且可能经由Caveolae从心肌细胞分泌。初步数据显示，心肌细胞特异性Cav-3过表达产生一种心脏表型，在基线时左心室中ANP表达显著增加，在左心室压力超负荷时心脏肥大减少，存活率增加，心脏功能保留。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。目的1：确定Cav-3调节心脏肥大和心力衰竭中ANP和ANP偶联信号传导的机制。目标二：将确定Cav-3的条件性心肌细胞特异性过表达是否调节ANP并改善压力超负荷诱导的心力衰竭。目的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大和心力衰竭的临床相关模型的研究，以关注机制并产生重要的临床前数据，以支持caveolin作为心力衰竭患者的新型治疗药物的潜在临床试验。 公共卫生相关性： 慢性高血压和缺血性心脏病等常见心血管疾病导致心脏肥大和充血性心力衰竭。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份列出心力衰竭。心力衰竭是VA质量增强研究计划（QUERI）的主要焦点，并且仍然是VA医疗保健系统中的头号出院诊断。本提案中描述的工作重点在于阐明支持使用小窝蛋白作为心力衰竭患者的新型治疗靶点的机制，并且与VA患者护理使命相关。