Caveolins and Heart Failure

项目总结(见说明)： 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。我们团队和其他人最近的工作表明，小窝蛋白，一种参与多种细胞功能的结构蛋白，包括细胞生长和肥大，可能是心力衰竭治疗的新靶点。我们实验室的工作表明，肌肉特异的小窝蛋白亚型，小窝蛋白-3(Cav-3)是保护心肌免受心肌应激的关键分子。此外，我们最近还发现，在心力衰竭的横动脉缩窄(TAC)模型中，心肌细胞特异性的Cav-3过表达(Cav-3 OE)可以增加存活率并增强心功能。Cav-3减轻心力衰竭的确切机制仍有待阐明，也是当前研究的重点。小窝是脂筏的一个特殊子集，富含胆固醇、鞘脂和小窝蛋白。现在已知小窝和小窝蛋白在肌膜和细胞质细胞器之间产生关键的相互作用，包括心肌细胞中的线粒体。线粒体功能障碍是心力衰竭进展的关键因素。已在线粒体膜上发现了小窝蛋白，但小窝蛋白的作用及其对线粒体功能的影响尚未被研究。我们开发了令人兴奋的新的初步数据，表明1)小窝和线粒体之间的密切关系因心肌应激而增加，2)Cav-3存在于心肌梗死的线粒体膜内。 3)Cav-3在心肌细胞中的过表达增加了线粒体内的Cav-3，改善了线粒体的功能；4)针对线粒体的Cav-3可以改善线粒体的功能，减少心肌细胞的氧化应激。基于这些令人信服的初步数据，我们将检验Cav-3可以通过调节线粒体功能来改变心力衰竭进展的假设。我们将利用最先进的分子生物学、成像技术、电子顺磁共振技术和心肌细胞生理学技术以及临床相关的心力衰竭模型，重点研究心力衰竭的机制，并产生重要的临床前数据，以支持小窝蛋白作为心力衰竭患者的新疗法的潜在用途。

PROJECT SUMMARY (See instructions): Heart failure remains a major public health problem and effective therapies are limited. Recent work by our group and others has suggested that caveolins, structured proteins involved in numerous cell functions including cell growth and hypertrophy may be novel targets for heart failure therapy. Work in our laboratory has shown that the muscle specific subtype of caveolin, Caveolin-3 (Cav-3) is a critical molecule in protecting the myocardium from myocardial stress. In addition, we have shown recently that cardiac myocyte-specific overexpression of Cav-3 (Cav-3 OE) produces increased survival and enhanced cardiac function in the transverse aortic constriction (TAC) model of heart failure. The precise mechanisms involved in the attenuation of heart failure by Cav-3 remain to be elucidated and are the focus of the current unit. Caveolae are a specialized subset of lipid rafts enriched in cholesterol, sphingolipids and caveolins. Caveolae and caveolins are now known to produce critical interactions between the sarcolemmal membrane and cytoplasmic organelles including mitochondria in cardiac myocytes. Mitochondrial dysfunction is a critical element of heart failure progression. Caveolins have been found in mitochondrial membranes, however the role of caveolins and their effects on mitochondrial function have not been investigated. We have developed exciting novel preliminary data that show 1) an intimate relationship between caveolae and mitochondria that is increased by myocardial stress, 2) the presence of Cav-3 within the inner mitochondrial membrane of mitochondria, 3) the overexpression of Cav-3 in cardiac myocytes increases Cav-3 within mitochondria and improves mitochondrial function, and 4) targeting Cav-3 specifically to mitochondria produces improved mitochondrial function and reduced oxidative stress in cardiac myocj1:es. Based on these compelling preliminary data we will test the hypothesis that Cav-3 can alter the progression of heart failure via modulation of mitochondrial function. We will use state of the art molecular biology, imaging technology, electron paramagnetic resonance technology and physiological techniques in cardiac myocytes and clinically relevant models of heart failure to focus on mechanism and produce important preclinical data to support the potential use of caveolins as novel therapeutics for heart failure patients.