Energetic State and Metabolic Remodeling in Cardiac Hypertrophy and Failure

病理性应激，如高血压和主动脉瓣狭窄患者左心室压力超负荷， 瓣膜狭窄，引起心脏肥大，是充血性心力衰竭的主要危险因素。肥大区和 衰竭的心脏将底物利用偏好从脂肪酸转移到葡萄糖、酮体等。 然而，能量状态和线粒体/代谢重塑之间的相互作用， 肥大和衰竭的机制仍不完全清楚。过去的研究大多是基于模型， 令人困惑的情况F1 Fo-ATP合酶是一种在体内产生ATP的必需酶复合物， 线粒体，从而在细胞能量学中发挥核心作用。F1 Fo-ATP合酶的遗传缺陷是罕见的 但由于扩张型心肌病和神经肌肉疾病而致命。那些患有部分 F1 Fo-ATP合酶缺陷对病理应激的反应尚不清楚。据记录，F1 Fo-ATP 合酶在来自患者和动物的病理性心脏中受损。我们最近的研究表明， 使用基因治疗增强F1 Fo-ATP合酶的结构/功能恢复了心脏功能， 肥大的心脏，证实了靶向F1 Fo-ATP合酶作为一种新的保护性治疗的概念 治疗心力衰竭我们先前的研究表明，缺乏F1 Fo-ATP合酶组装因子的小鼠，如 如ATPAF 1，导致心肌病F1 Fo-ATP合酶缺乏。因此，我们的中心假设是 增强F1 Fo-ATP合酶能力以促进ATP生产效率将减轻 线粒体疾病和随之而来的心脏肥大和衰竭。我们建议测试中央 假设有两个目的。在目标1中，我们将测试F1 Fo-ATP合酶缺乏是一种可解释的疾病。 心力衰竭进展的致病因素。实验将提供证据支持部分F1 Fo- ATP合酶缺乏导致心力衰竭的病理进展和基因治疗 纠正这种缺陷将减缓心力衰竭的进展。在目标2中，我们将定义F1 Fo-ATP 合成酶的能力直接与线粒体内稳态和代谢重塑相关， 成人心脏的心肌细胞。因此，该项目将提供明确的证据，以支持 创新的基因疗法，并确定基础机制。这项拟议中的研究将产生新的见解 心脏病理性肥大进展中代谢重塑的主要机制。 临床前动物研究将为创新的基因疗法奠定基础，这将大大提高 影响患者护理。

Pathological stresses, such as pressure overload in the left ventricles of patients with hypertension and aortic valve stenosis, cause cardiac hypertrophy, a major risk factor of congestive heart failure. Hypertrophic and failing hearts shift substrate utilization preference from fatty acids to glucose, ketone bodies, and others. However, the interplay between the energetic state and the mitochondrial/metabolic remodeling in the hypertrophic and failing remains incompletely understood. Most of the past studies are based on models with confounding conditions. F1Fo-ATP synthase is an essential enzyme complex that generates ATP in mitochondria, thus playing a central role in cellular energetics. Genetic defects of F1Fo-ATP synthase are rare but deadly because of dilated cardiomyopathy and neuromuscular disorders. How those patients with partial F1Fo-ATP synthase deficiencies respond to pathological stresses is unclear. It is documented that F1Fo-ATP synthase is impaired in pathological hearts from patients and animals. Our recent study revealed that enhancing F1Fo-ATP synthase structure/function using gene therapy restored cardiac function in the hypertrophied hearts, corroborating the concept of targeting F1Fo-ATP synthase as a novel protective therapy for heart failure. Our prior studies demonstrated that mice lacking F1Fo-ATP synthase assembly factors, such as ATPAF1, lead to F1Fo-ATP synthase deficiencies with cardiomyopathy. Therefore, our central hypothesis is that enhancing F1Fo-ATP synthase capacity to facilitate ATP production efficiency will mitigate mitochondrial disorders and the ensued cardiac hypertrophy and failure. We propose to test the central hypothesis with two aims. In aim 1, we will test that the F1Fo-ATP synthase deficiency is an amendable pathogenic factor in heart failure progression. Experiments will provide evidence to support that partial F1Fo- ATP synthase deficiency contributes to the pathological progression of heart failure, and gene therapies correcting the deficiency will slow the heart failure progression. In aim 2, we will define how F1Fo-ATP synthase capacities directly correlate to mitochondrial homeostasis and metabolic remodeling in cardiomyocytes of the adult heart. Therefore, this proposed project will provide definitive evidence to support innovative gene therapy and define the underpinning mechanisms. The proposed study will yield novel insights into the primary mechanisms underlying metabolic remodeling in cardiac pathological hypertrophy progression. The preclinical animal study will lay the groundwork for innovative gene therapies, which will significantly impact patient care.