Mitochondrial Permeability Transition as a Target for Cardioprotection in Heart F

线粒体通透性转变作为心脏 F 心脏保护的目标

• 批准号: 8337107
• 负责人: Sabzali Javadov
• 金额: $ 25.34万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-22 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8337107
• 关键词: 5' -AMP-activated protein kinase; Acetylation; Adenine Nucleotide Translocase; Affect; Aftercare; Animal Model; Apoptosis; Biogenesis; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cell model; Cells; Collagen; Complex; Cyclosporine; Development; Diagnosis; Down-Regulation; Effector Cell; Equilibrium; Evolution; Extracellular Matrix; Fibroblasts; Fibrosis; Financial compensation; Functional disorder; Genetic; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Hypertrophy; Immunosuppressive Agents; Infarction; Inflammation; Injury; Inner mitochondrial membrane; Ischemia; Ischemic Preconditioning; Lead; Life; Mediating; Metabolic; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Myocardial; Myocardial Infarction; Necrosis; Outer Mitochondrial Membrane; PPAR alpha; Pathway interactions; Patients; Permeability; Peroxisome Proliferator-Activated Receptors; Play; Prevention; Propofol; Proteins; Rattus; Regulation; Reperfusion Therapy; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Techniques; Testing; Translating; United States; Ventricular Remodeling; Voltage-Dependent Anion Channel; Workload; attenuation; cyclophilin D; experience; genetic regulatory protein; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; mitochondrial dysfunction; mitochondrial permeability transition pore; mortality; novel therapeutics; prevent; protective effect; response; sanglifehrin A; stressor; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Cardiac remodeling following myocardial infarction is the initial myocardial hypertrophic response which follows myocardial injury and the eventual evolution to heart failure. Attenuation of the early adaptive hypertrophy can be translated into attenuation of heart failure response such that understanding the molecular and cellular mechanisms underlying progression of cardiac remodeling to heart failure is of crucial importance. Mitochondrial dysfunction is central to the loss of contractile function during ventricular remodeling/heart failure that are thought to be induced as a result of inactivation of cell signaling molecules, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR) coactivator-1alpha (PGC-1alpha). Mitochondrial permeability transition pore (MPTP) opening has been shown to be an end-effector for cell death that is associated with increased mitochondrial fragmentation due to alterations in the balance between fission and fusion of mitochondria. In this proposal, we hypothesize that the alterations in the AMPK/PGC-1alpha cascade trigger MPTP opening leading to cardiac dysfunction in post-infarction cardiac remodeling; modulation of the MPTP occurs through a direct interaction of AMPK/PGC-1alpha with the pore complex and/or indirectly, through AMPK-induced acetylation of cyclophilin D. To test our hypothesis we will study the intact heart, cultured cardiomyocytes and isolated mitochondria using an in vivo rat model of post-infarction remodeling and an in vitro model of rat cardiomyocyte hypertrophy. We have extensive experience with the proposed animal and cell models, and the necessary techniques to study mitochondrial function in cardiac diseases, and develop new pharmacological and conditional strategies for cardioprotection. The specific aims of this proposal are to: (1) Examine whether progression of post-infarction remodeling to heart failure is associated with increased MPTP opening and mitochondrial fragmentation; (2) Determine whether MPTP formation is regulated by the AMPK/PPARalpha pathway in cardiac remodeling; (3) Define whether inhibition of MPTP has long-term protective effects during post-infarction remodeling. The proposed studies will identify the specific mitochondrial adaptations and alterations, and help develop new therapeutic strategies for treatment of post-myocardial infarction heart failure. PUBLIC HEALTH RELEVANCE: The proposed studies are aimed at elucidating the mechanisms involved in mitochondria-mediated cardiac dysfunction with progression of post-infarction remodeling to heart failure. Particularly, the relationship between mitochondrial permeability transition pore (MPTP) opening/mitochondrial fragmentation and cardiac dysfunction will be investigated in an in vivo model of post-infarction cardiac remodeling and an in vitro model of cardiomyocyte hypertrophy. Since the mitochondria play a critical role in cell death through apoptosis and necrosis, prevention or reversal of MPTP opening is crucial to protect the heart against cardiac diseases. Therefore, the cardioprotective effects of the specific inhibitor for the main MPTP regulatory protein cyclophilin D, sanglifehrin A will be used in the present study to guard the heart against ventricular remodeling/heart failure.

描述（由申请人提供）：心肌梗死后的心脏重塑是心肌损伤后的初始心肌肥大反应，最终演变为心力衰竭。早期适应性肥大的减弱可以转化为心力衰竭反应的减弱，因此了解心脏重塑进展为心力衰竭的分子和细胞机制至关重要。线粒体功能障碍是心室重塑/心力衰竭期间收缩功能丧失的核心，被认为是细胞信号分子AMP活化蛋白激酶（AMPK）和过氧化物酶体增殖物活化受体（PPAR）共激活因子-1 α（PGC-1 α）失活的结果。线粒体渗透性转换孔（MPTP）开放已被证明是细胞死亡的末端效应物，其与由于线粒体的分裂与融合之间的平衡的改变而增加的线粒体碎片化相关。在这个提议中，我们假设AMPK/PGC-1 α级联的改变触发MPTP开放，导致梗死后心脏重塑中的心功能障碍; MPTP的调节通过AMPK/PGC-1 α与孔复合物的直接相互作用和/或通过AMPK诱导的亲环素D乙酰化间接发生。为了验证我们的假设，我们将研究完整的心脏，培养的心肌细胞和分离的线粒体，使用在体内大鼠模型的梗死后重塑和在体外模型的大鼠心肌细胞肥大。我们在所提出的动物和细胞模型方面拥有丰富的经验，并拥有必要的技术来研究心脏疾病中的线粒体功能，并开发新的药理学和条件性心脏保护策略。本提案的具体目的是：（1）检查梗死后重构进展至心力衰竭是否与MPTP开放增加和线粒体碎片化相关;（2）确定MPTP形成是否受心脏重构中AMPK/PPARalpha通路的调节;（3）确定MPTP抑制是否在梗死后重构期间具有长期保护作用。拟议的研究将确定特定的线粒体适应和改变，并帮助开发新的治疗策略，用于治疗心肌梗死后心力衰竭。 公共卫生关系：这些研究旨在阐明心肌梗死后重构进展为心力衰竭的心肌梗死介导的心功能不全的机制。特别地，将在梗死后心脏重塑的体内模型和心肌细胞肥大的体外模型中研究线粒体通透性转换孔（MPTP）开放/线粒体断裂与心脏功能障碍之间的关系。由于线粒体通过凋亡和坏死在细胞死亡中起关键作用，因此预防或逆转MPTP开放对于保护心脏免受心脏疾病至关重要。因此，特异性抗氧化剂的心脏保护作用 主要MPTP调节蛋白亲环素D的抑制剂sanglifehrin A将用于本研究以保护心脏免于心室重构/心力衰竭。