Energetic State and Metabolic Remodeling in Cardiac Hypertrophy and Failure

心脏肥大和衰竭的能量状态和代谢重塑

• 批准号: 10522598
• 负责人: QINGLIN YANG
• 金额: $ 49.12万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-14 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522598
• 关键词: Acute; Adult; Aerobic; Animals; Aortic Valve Stenosis; Biogenesis; Cardiac; Cardiac Myocytes; Cardiac development; Cardiomyopathies; Cause of Death; Congestive Heart Failure; Consumption; Cytosol; Defect; Development; Diabetes Mellitus; Dilated Cardiomyopathy; Disease; Embryo; Etiology; Fatty Acids; Fibroblasts; Foundations; Functional disorder; Glucose; Heart; Heart Hypertrophy; Heart failure; Homeostasis; Hypertension; Hypertrophy; Impairment; Inherited; Ketone Bodies; Knowledge; Lead; Left; Left ventricular structure; Mediating; Metabolic; Metabolism; Mitochondria; Mitochondrial Diseases; Modeling; Molecular Machines; Morphology; Multienzyme Complexes; Mus; Mutation; Myocardial; Myocardial dysfunction; Neuromuscular Diseases; Oxidative Phosphorylation; Pathologic; Patient Care; Patients; Performance; Physiologic intraventricular pressure; Play; Production; Pump; Rattus; Respiration; Risk Factors; Role; Side; Stress; Structure; System; Testing; Therapeutic; Virulence Factors; advanced disease; base; effective intervention; effective therapy; efficacy testing; experimental study; gene therapy; heart function; improved; innovation; insight; mortality; new therapeutic target; novel; oligomycin sensitivity-conferring protein; oxidation; pre-clinical; preference; pressure; protective effect; targeted treatment; therapeutic development

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.

高血压病患者左心室压力超负荷等病理性应激反应 瓣膜狭窄，导致心脏肥厚，是充血性心力衰竭的主要危险因素。肥厚性和 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 肥大和衰竭仍未完全了解。过去的大多数研究都是基于 令人困惑的状况。F1Fo-ATP合成酶是一种在体内产生ATP的重要酶复合体 线粒体，因此在细胞能量学中起着核心作用。F1Fo-ATP合酶基因缺陷罕见 但由于扩张型心肌病和神经肌肉疾病而致命。那些部分的患者是如何 F1Fo-ATP合酶缺陷对病理性应激的反应尚不清楚。据文献记载，F1Fo-ATP 合酶在病人和动物的病理性心脏中受到损害。我们最近的研究表明， 基因治疗增强F1Fo-ATP合酶结构/功能恢复心功能 肥厚的心脏，证实了靶向F1Fo-ATP合成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F1Fo-ATP合成酶组装因子的小鼠，如 作为ATPAF1，导致心肌病的F1Fo-ATP合酶缺陷。因此，我们的中心假设是 提高F1Fo-ATP合成酶能力以促进ATP生产效率将缓解 线粒体紊乱和随之而来的心肌肥大和衰竭。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F1Fo-ATP合成酶缺陷是一种可修正的 心力衰竭进展中的致病因素。实验将提供证据支持部分F1Fo- 三磷酸腺苷合成酶缺乏症与心力衰竭的病理进展及基因治疗 纠正这一不足将减缓心力衰竭的进展。在目标2中，我们将定义F1Fo-ATP如何 合酶活性与线粒体动态平衡和代谢重塑直接相关 成人心脏的心肌细胞。因此，这个拟议的项目将提供确凿的证据来支持 创新的基因疗法，并定义支撑机制。这项拟议的研究将产生新的见解 探讨心脏病理性肥厚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，这将显著 影响患者护理。