Metabolic Adaptation and Functional Recovery of Hibernating Myocardium

描述(申请人提供)：血管重建术改善冬眠心肌患者的功能和预后，但残留的左心室功能障碍是常见的。导致这种情况的机制尚不清楚，但这种功能障碍与心肌瘢痕形成的程度不成比例，增加了它反映残留的心肌细胞重塑的可能性。在之前的资助期间，我们证明了从慢性顿抑到冬眠心肌的进展伴随着凋亡诱导的心肌细胞丢失、代偿性心肌细胞肥大和降低局部能量利用的代谢适应。虽然蛋白质组图谱类似于胎儿和衰竭的心肌细胞，但局部功能和代谢的下调限制了氧化应激，最终阻止了进一步的细胞凋亡。在更新应用中，我们将确定维持心肌细胞活性的对缺血的代谢适应是否最终限制了血运重建后的功能恢复。我们提出了一种并行的生理学、蛋白质组学和线粒体功能研究的翻译方法，对存活的慢性功能障碍的猪进行研究。蛋白质组学分析将用于在已建立的无明显纤维化的存活功能障碍心肌的猪模型中识别候选线粒体蛋白。这些将与线粒体呼吸和候选酶活性的体外功能分析相结合。类似于用于患者的治疗干预将使我们能够识别导致适应的分子通路的可塑性，并确定它们在残余收缩功能障碍中的重要性。目的1验证线粒体蛋白表达和功能的局部改变区分冬眠和慢性顿抑心肌的假说。目的2验证线粒体和收缩功能障碍在经皮冠状动脉血运重建术后持续存在的假说，并决定功能恢复的时间进程。目的3验证冠状动脉内应用AdvFGF5(可使线粒体蛋白质组改变正常化并独立于血管生成改善功能)可加速和增强血管重建后功能恢复的假说。我们的长期目标是利用这项研究开发新的策略来逆转缺血性心肌病患者的心肌功能障碍，从而减少因心力衰竭和猝死而导致的死亡和残疾。

DESCRIPTION (provided by applicant): Revascularization improves function and prognosis in patients with hibernating myocardium yet residual LV dysfunction is common. The mechanisms responsible for this are unclear but the dysfunction is disproportionate to the degree of myocardial scarring raising the possibility that it reflects residual myocyte cellular remodeling. During the previous funding period, we demonstrated that the progression from chronically stunned to hibernating myocardium is accompanied by apoptosis-induced myocyte loss, compensatory myocyte hypertrophy and metabolic adaptations that reduce regional energy utilization. While the proteomic profile is similar to the fetal and failing myocyte, the downregulation in regional function and metabolism limits oxidative stress to ultimately prevent further apoptosis. In the renewal application, we will determine whether the metabolic adaptations to ischemia which preserve myocyte viability ultimately limit functional recovery after revascularization. We propose a translational approach with parallel physiological, proteomic and mitochondrial functional studies in swine with viable chronically dysfunctional myocardium. Proteomic profiling will be used to identify candidate mitochondrial proteins in established swine models of viable dysfunctional myocardium that do not have significant fibrosis. These will be coupled with in vitro functional assays of mitochondrial respiration and candidate enzyme activity. Therapeutic interventions similar to those used in patients will allow us to identify plasticity in the molecular pathways responsible for adaptation and determine their importance in residual contractile dysfunciton. Aim 1 tests the hypothesis that regional alterations in mitochondrial protein expression and function distinguish hibernating from chronically stunned myocardium. Aim 2 tests the hypothesis that mitochondrial and contractile dysfunction persist after percutaneous coronary revascularization and determines the time course of functional recovery. Aim 3 tests the hypothesis that hybrid therapy with intracoronary AdvFGF-5 (which normalizes mitochondrial proteomic changes and improves function independently of angiogenesis) accelerates and enhances functional recovery after revascularization. Our long-term objective is to use this research to develop new strategies to reverse myocardial dysfunction in patients with ischemic cardiomyoapthy which will reduce death and disability from heart failure and sudden death.