Targeting Energetics to Improve Outcomes in Hypertrophic Cardiomyopathy

靶向能量药物以改善肥厚型心肌病的预后

• 批准号: 10687401
• 负责人: Ivan Luptak
• 金额: $ 81.76万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687401
• 关键词: ATP Hydrolysis; ATP Synthesis Pathway; ATP phosphohydrolase; Acute; Address; Affect; Age; American; Antidiabetic Drugs; Arrhythmia; Butyrates; Cardiac; Cardiology; Cardiovascular system; Chemicals; Clinical; Consumption; Data; Defect; Development; Diabetes Mellitus; Disease; Early Diagnosis; Echocardiography; Excision; Fibrosis; Free Energy; Functional disorder; Genes; Genetic; Glucose; Growth; Heart; Heart Hypertrophy; Heart failure; Hereditary Disease; Hypertrophic Cardiomyopathy; Hypertrophy; Image; Impairment; Intervention; Ion Pumps; Knowledge; Left Ventricular Hypertrophy; Link; Magnetic Resonance Spectroscopy; Measurement; Measures; Mitochondria; Mitochondrial Proteins; Mus; Muscle Cells; Mutation; Myocardial; Myocardium; Myosin ATPase; Na(+)-K(+)-Exchanging ATPase; Nonmuscle Myosin Type IIA; Outcome; Oxidative Stress; Pathogenicity; Pathway interactions; Perfusion; Persons; Phase; Phenotype; Phosphorus; Process; Production; Protein Biosynthesis; Reactive Oxygen Species; Relaxation; Risk; Sarcomeres; Sodium; Sodium Phosphorus; Structure; Testing; Troponin T; Work; base; catalase; clinical development; clinical phenotype; coronary fibrosis; cost; diabetic cardiomyopathy; drinking water; drug development; effective therapy; energy balance; heart function; hemodynamics; improved; improved functioning; improved outcome; in vivo magnetic resonance spectroscopy; inhibitor; interest; mouse model; overexpression; protein function; research clinical testing; small molecule; sudden cardiac death; tool

PROJECT SUMMARY. Despite recent exponential growth of the field of cardiovascular genetics leading to iden- tification of hundreds of mutations responsible for hypertrophic cardiomyopathy (HCM), the mechanism linking sarcomeric mutations to the clinical phenotype remains unknown. Clinical features of HCM are severe left ven- tricular hypertrophy, myocardial fibrosis, diastolic dysfunction, and an increased risk of arrhythmias and heart failure. As there is no disease-modifying therapy available, HCM remains the most common cause of sudden cardiac death in the young. This proposal considers worsened myocardial energetics as the unknown shared pathway that, when triggered by a sarcomeric mutation, leads to the development of the clinical phenotype. Mutations responsible for HCM increase power of contraction in extremely inefficient way, resulting in several- fold increased ATP demand. Mitochondria initially meet the increased demand and maintain normal ATP con- centration, albeit at a cost of accumulation of ADP, a product of ATP hydrolysis. Elevated ADP limits free energy of ATP hydrolysis (∆G~ATP), which is the amount of chemical energy in ATP that ATPases can use to perform work. Decreased ∆G~ATP inhibits ion pumps SERCA and Na+/K+ ATPase leading to increased diastolic Ca++ and intracellular [Na+]i, associated with diastolic dysfunction and arrhythmias. Moreover, elevated [Na+]i further impairs mitochondrial ATP synthesis and increases reactive oxygen species (ROS) production. Excessive ROS, in turn, oxidatively inhibit mitochondrial proteins and ATP synthesis. Thus, even though the primary defect is in the inefficient sarcomere, mitochondrial damage ensues, establishing a vicious cycle of energy shortage. The central hypothesis of this proposal is that interventions that improve energy balance, result in improved function, hypertrophy and fibrosis in HCM. The central hypothesis will be tested by pursuing two mechanisms to improve energetics in HCM: 1) decreasing ATP demand and 2) improving mitochondrial ATP synthesis. Sodium and phosphorus magnetic resonance spectroscopy and imaging will determine the interplay between myocardial [Na+]i, ROS, contractile function, energetics, hypertrophy and fibrosis in a murine models of HCM bearing two of the most lethal mutations, R403Q in myosin and R92L in troponin T. Specific Aim 1 will test the hypothesis that treatment with a myosin ATPase inhibitor, MYK-461, decreases excessive ATP consumption to improve ∆G~ATP, [Na+]i, oxidative stress and cardiac function in HCM mice. Specific Aim 2 will test the hypothesis that interventions that increase mitochondrial ATP synthesis improve ∆G~ATP, diastolic function and contractile re- serve in HCM. ATP synthesis in HCM mice will be increased by a) saturating mitochondria with an accessible substrate, butyrate, b) supressing excessive mitochondrial ROS by overexpressing mitochondrial catalase, and c) decreasing intracellular [Na+]i with empagliflozin, a Na+/glucose cotransport (SGLT2) inhibitor. These results will provide immediately translatable tools to modify the disease process in HCM. Moreover, they will guide drug development in spectrum of mitochondria-based cardiovascular conditions beyond HCM.

项目摘要。尽管最近心血管遗传学领域呈指数级增长，但 导致肥厚型心肌病 (HCM) 的数百种突变的作用，其机制将 HCM 的临床表型的肌节突变仍不清楚。 三尖瓣肥大、心肌纤维化、舒张功能障碍以及心律失常和心脏病的风险增加 由于没有可用的疾病缓解疗法，HCM 仍然是突发的最常见原因。 该提案将心肌能量恶化视为未知的共同因素。 当由肌节突变触发时，会导致临床表型的发展。 导致 HCM 的突变以极其低效的方式增加了收缩能力，导致了几种- 线粒体最初满足增加的 ATP 需求并维持正常的 ATP 浓度。 集中，尽管以 ADP 的积累为代价，ADP 是 ATP 水解的产物，升高的 ADP 限制了自由能。 ATP 水解 (ΔG~ATP)，这是 ATP 酶可用于执行的 ATP 化学能的量 减少的 ΔG~ATP 抑制离子泵 SERCA 和 Na+/K+ ATP 酶，导致舒张期 Ca++ 增加。 和细胞内 [Na+]i，与舒张功能障碍和心律失常相关。此外，[Na+]i 进一步升高。 损害线粒体 ATP 合成并增加活性氧 (ROS) 的产生。 反过来，氧化抑制线粒体蛋白质和 ATP 合成，因此，尽管主要缺陷在于。 如果肌节效率低下，线粒体就会受损，形成能量短缺的恶性循环。 该提案的中心假设是改善能量平衡的干预措施，导致功能改善， HCM 中的肥大和纤维化将通过两种机制来检验。 HCM 中的能量学：1) 减少 ATP 需求，2) 改善线粒体 ATP 合成。 磷磁共振波谱和成像将确定心肌之间的相互作用 [Na+]i、ROS、收缩功能、能量学、肥大和纤维化在具有两种 HCM 的小鼠模型中 最致命的突变，肌球蛋白中的 R403Q 和肌钙蛋白 T 中的 R92L。特定目标 1 将检验假设 使用肌球蛋白 ATP 酶抑制剂 MYK-461 治疗可减少过度的 ATP 消耗，从而改善 HCM 小鼠的 ΔG~ATP、[Na+]i、氧化应激和心脏功能将检验以下假设： 增加线粒体 ATP 合成的干预措施可改善 ΔG~ATP、舒张功能和收缩功能 HCM 小鼠中的 ATP 合成将通过 a) 使线粒体饱和而增加。 底物，丁酸盐，b) 通过过表达线粒体过氧化氢酶来抑制过量的线粒体 ROS，以及 c) 使用恩格列净（一种 Na+/葡萄糖协同转运 (SGLT2) 抑制剂）减少细胞内 [Na+]i 这些结果。 将提供可立即转化的工具来改变 HCM 的疾病过程，此外，它们还将指导药物。 HCM 之外基于线粒体的心血管疾病谱的发展。