Metabolic mechanisms of cardioprotection through alpha-1A adrenergic receptor activation

通过 α-1A 肾上腺素受体激活保护心脏的代谢机制

• 批准号: 10587727
• 负责人: Brian C Jensen
• 金额: $ 58.51万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587727
• 关键词: Adrenergic Receptor; Agonist; Anthracycline; Bioenergetics; Cardiac; Cardiac Myocytes; Cardiomyopathies; Carnitine; Cell Death Induction; Cell Respiration; Chronic; Clinical; Complex; Consumption; Coupled; Coupling; Data; Defect; Duchenne muscular dystrophy; Electron Transport; Energy Supply; Enzymes; Exhibits; Functional disorder; Heart; Heart failure; High Fat Diet; Impairment; In Vitro; Infusion procedures; Injury; Isoproterenol; Knock-out; Knockout Mice; Maintenance; Measures; Mediating; Mediator; Metabolic; Metabolism; Mitochondria; Modeling; Mus; Muscle Fibers; Muscle Mitochondria; Myocardial; Myocardial Infarction; Myocardium; Nervous System control; Organ; Oxidative Phosphorylation; Palmitates; Pathologic; Permeability; Pharmaceutical Preparations; Physiological; Proteins; Proteomics; Publishing; Receptor Activation; Receptors, Adrenergic, beta-1; Regulation; Research Personnel; Resolution; Skeletal Muscle; Spirometry; Sympathetic Nervous System; Testing; Toxic effect; Transferase; Treatment Failure; alpha-1 adrenergic receptors; antagonist; aorta constriction; cardiometabolism; cardioprotection; clinically relevant; differential expression; effective therapy; enzyme activity; experimental study; fatty acid oxidation; gain of function; in vivo; lipidomics; long chain fatty acid; loss of function; mouse model; novel; preservation; prevent; stable isotope

The heart consumes more ATP than any other organ, the vast majority of which is generated by fatty acid oxidation (FAO) coupled to oxidative phosphorylation (OXPHOS) in mitochondria. The sympathetic nervous system (SNS) regulates numerous aspects of mitochondrial function through activation of alpha-1-adrenergic receptors (α1-ARs) and beta-ARs (β-ARs) in cardiomyocytes, as we recently reviewed. Persistent stimulation of cardiac β-ARs causes pathological structural and metabolic changes resulting in myocardial energy depletion and heart failure (HF), but α1-ARs exert adaptive effects in the failing heart, mitigating the toxicity of chronic β-AR activation. The mechanisms underlying this cardioprotection remain largely unclear. There are three α1-AR subtypes: A, B, and D. Mounting evidence indicates that the α1A subtype protects cardiomyocytes against multiple types of injury. We previously published that a selective α1A agonist increases ATP content in anthracycline-exposed failing mouse hearts. Our preliminary data now show that permeabilized cardiac muscle fibers and isolated mitochondria from knockout mice lacking the αA-AR (α1AKO) exhibit decreased FAO and diminished activity of electron transport chain (ETC) Complex I and II. We also recently found that treatment with a selective α1A agonist enhances Complex I, II and IV activity in uninjured mouse hearts and protects cardiac energetic capacity and contractile function in mice subjected to experimental myocardial infarction. Collectively, these findings suggest a novel mechanism for α1A-mediated cardioprotection, as regulation of neither FAO nor OXPHOS by β1-ARs has been studied previously. We now propose three Specific Aims to build upon our published findings and novel preliminary data to test the central hypothesis that α1A-ARs metabolically support the uninjured heart and protect the failing heart by enhancing mitochondrial oxidative capacity. Aim 1 will determine whether α1A-ARs enhance OXPHOS in the heart through cardiomyocyte-autonomous effects using our cardiomyocyte-specific β1A knockout mice, novel focused studies of α1A skeletal muscle FAO regulation, and a high fat diet model. Aim 2 will find if α1A-ARs preserve energetic capacity through maintenance of long chain FAO and regulation of ETC enzyme activity, coupling in vivo profiling of α1A knockout and α1A agonist treated mouse hearts with mechanistic in vitro approaches. Aim 3 will test whether selective α1A-AR agonists act as mitotropes—drugs that enhance mitochondrial function--to protect against HF using three clinically relevant mouse models: chronic isoproterenol infusion, cardiomyocyte-specific loss of FAO (Carnitine palmitoyl transferase 2 knockout), and a Duchenne Muscular Dystrophy model in which Complex I activity is impaired. If successfully completed, the proposed experiments have the potential to significantly expand our understanding of SNS regulation of cardiomyocyte mitochondrial function, elucidating new mechanisms of α1A-mediated cardioprotection in clinically and physiologically relevant mouse models. These studies also represent the next step in our ongoing efforts to advance α1A-AR agonists as novel HF therapies.

心脏消耗的ATP比任何其他器官都多，其中绝大多数是由线粒体中的脂肪酸氧化（FAO）和氧化磷酸化（OXPHOS）产生的。交感神经系统（SNS）通过激活心肌细胞中的α 1肾上腺素能受体（α1-AR）和β-AR（β-AR）来调节线粒体功能的许多方面。心脏β-AR的持续刺激引起病理结构和代谢变化，导致心肌能量消耗和心力衰竭（HF），但α1-AR在衰竭心脏中发挥适应性作用，减轻慢性β-AR激活的毒性。这种心脏保护的机制在很大程度上仍不清楚。α1-AR有三种亚型：A、B和D。越来越多的证据表明，α1A亚型保护心肌细胞免受多种类型的损伤。我们先前发表了选择性α1A激动剂增加蒽环类药物暴露的衰竭小鼠心脏中的ATP含量。我们的初步数据现在表明，从缺乏αA-AR（α1AKO）的敲除小鼠中分离的透化心肌纤维和线粒体表现出FAO减少和电子传递链（ETC）复合物I和II活性降低。我们最近还发现，用选择性α1A激动剂治疗可增强未受伤小鼠心脏中复合物I、II和IV的活性，并保护实验性心肌梗死小鼠的心脏能量和收缩功能。总的来说，这些研究结果表明α 1A介导的心脏保护的新机制，因为之前已经研究了β1-AR对FAO或OXPHOS的调节。我们现在提出了三个具体目标，以我们已发表的研究结果和新的初步数据为基础，来检验中心假设，即α 1A-AR通过代谢支持未受伤的心脏，并通过增强线粒体氧化能力来保护衰竭的心脏。目的1将使用我们的心肌细胞特异性β1A基因敲除小鼠、α1A骨骼肌FAO调节的新焦点研究和高脂饮食模型来确定α1A-ARs是否通过心肌细胞自主效应增强心脏中的OXPHOS。目的2将α1A基因敲除和α1A激动剂处理的小鼠心脏的体内分析与体外机制方法相结合，研究α1A-ARs是否通过维持长链FAO和调节ETC酶活性来保持能量能力。目的3将测试选择性α1A-AR激动剂是否作为促分裂剂-增强线粒体功能的药物-使用三种临床相关的小鼠模型来预防HF：慢性异丙肾上腺素输注，心肌细胞特异性FAO损失（肉毒碱棕榈酰转移酶2敲除）和Duchenne肌营养不良模型，其中复合物I活性受损。如果成功完成，拟议的实验有可能显着扩大我们对SNS调节心肌细胞线粒体功能的理解，阐明临床和生理相关小鼠模型中α 1A介导的心脏保护的新机制。这些研究也代表了我们正在努力推进α1A-AR激动剂作为新型HF治疗的下一步。