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: 7931351
• 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/7931351
• 关键词: Address; Adrenergic Agonists; Animal Model; Atrial Natriuretic Factor; Binding; Cardiac; Cardiac Myocytes; Cardiomyopathies; Caveolae; Caveolins; Cell Surface Receptors; Cell physiology; Clinical Trials; Complex; Coupled; Data; Diuretics; Endothelin-1; Family suidae; Gene Expression; Gene Transfer; Genes; Heart Atrium; Heart Hypertrophy; Heart failure; Hypertrophy; Knock-out; Left; Left ventricular structure; Lipids; Modeling; Molecular; Mus; Muscle; Muscle Cells; Myocardium; Natriuretic Peptides; Nuclear; Patients; Phenotype; Physiologic intraventricular pressure; Physiological; Pre-Clinical Model; Property; Protein Isoforms; Public Health; Receptor Signaling; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Stimulus; Structural Protein; Techniques; Ventricular; abstracting; base; caveolin-3; cell growth; clinically relevant; design; effective therapy; novel therapeutics; nuclear factor 1; overexpression; pre-clinical; pressure; programs; saluretic; Address; Adrenergic Agonists; Animal Model; Atrial Natriuretic Factor; Binding; Cardiac; Cardiac Myocytes; Cardiomyopathies; Caveolae; Caveolins; Cell Surface Receptors; Cell physiology; Clinical Trials; Complex; Coupled; Data; Diuretics; Endothelin-1; Family suidae; Gene Expression; Gene Transfer; Genes; Heart Atrium; Heart Hypertrophy; Heart failure; Hypertrophy; Knock-out; Left; Left ventricular structure; Lipids; Modeling; Molecular; Mus; Muscle; Muscle Cells; Myocardium; Natriuretic Peptides; Nuclear; Patients; Phenotype; Physiologic intraventricular pressure; Physiological; Pre-Clinical Model; Property; Protein Isoforms; Public Health; Receptor Signaling; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Stimulus; Structural Protein; Techniques; Ventricular; abstracting; base; caveolin-3; cell growth; clinically relevant; design; effective therapy; novel therapeutics; nuclear factor 1; overexpression; pre-clinical; pressure; programs; 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/抽象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，有效的疗法受到限制。与心脏肥大有关的分子信号传导很复杂，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包含细胞表面受体和细胞内信号分子的微区域的概念，并为信号通路提供了顺序。 Caveolae是含有结构蛋白，结合，组织和调节受体以及参与许多细胞功能（包括细胞生长和肥大）的信号分子的专门微域。淘汰小窝蛋白（Caveolin-3，cav-3）的肌肉特异性同工型的基因会导致心脏肥大和心肌病。相反，心肌细胞中CAV-3的过表达阻断肾上腺素能激动剂和内皮素-1诱导肌细胞肥大。因此，CAV-3的丧失足以诱导分子程序，导致心脏肥大和心肌病和CAV-3的过表达可能是负调节心脏肥大的一种手段。心房尿液肽（ANP）具有抑制心脏肥大的利尿剂，发铁和血管舒张特性。将近二十年前提出了ANP，Caveolae和Caveolins之间的关系。 ANP存在于Caveolae中，与CAV-3密切相关，可以通过心脏心肌细胞的小窝分泌。初步数据表明，CAV-3的心肌细胞特异性过表达产生心脏表型，基线时ANP的表达急剧增加，心脏肥大降低，生存率增加并在左心室压力超负荷的情况下保留了心脏肥大并保留了心脏功能。该提案旨在解决以下假设：CAV-3调节ANP表达以减少心脏肥大和心力衰竭，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而有益的手段。将追求以下目标：目标1：将确定心肥大和心力衰竭中ANP和ANP耦合信号的调节机制。 AIM 2：将确定CAV-3的有条件心肌细胞特异性过表达是否会调节ANP并改善压力超负荷引起的心力衰竭。 AIM 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。在大型和小动物模型的临床相关模型和心力衰竭模型的研究中，将使用最先进的分子和生理技术，以专注于机制，并产生重要的临床前数据，以支持针对小窝蛋白的潜在临床试验，作为对心力衰竭患者的新型疗法。 公共卫生相关性： 项目叙事流行的心血管疾病（如慢性高血压和缺血性心脏病）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和生活质量差有关。心力衰竭影响了近500万美国人，在美国每8个死亡人数认证中，有1个被列入。心力衰竭是VA质量增强研究计划（QUERI）的主要重点，并且仍然是VA医疗保健系统中的第一排放诊断。该提案中描述的工作着重于阐明可爱素蛋白作为心力衰竭患者的新型治疗靶点的机制，并且与VA患者护理任务相关。