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: 8676936
• 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/8676936
• 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.

描述（由申请人提供）：心肌梗死后心脏重塑是心肌损伤后的最初心肌肥大反应，最终导致心力衰竭。早期自适应肥大的衰减可以转化为心力衰竭反应的衰减，以便了解心脏重塑对心力衰竭进展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关键，被认为是由于细胞信号分子失活，AMP激活的蛋白激酶（AMPK）和过氧化物酶体增殖物激活受体（PPAR）辅酶的诱导而诱导的。线粒体通透性过渡孔（MPTP）开口已被证明是细胞死亡的终极效应，这与线粒体碎片增加有关，这是由于线粒体平衡和线粒体融合之间的平衡改变而导致的。在此提案中，我们假设AMPK/PGC-1Alpha级联反应的变化触发了MPTP开放，导致心脏后重塑后心脏功能障碍。 MPTP的调节是通过AMPK/PGC-1Alpha与孔复合物的直接相互作用和/或间接的，通过AMPK诱导的环粒蛋白D的乙酰化D发生。为了测试我们的假设，我们将研究完整的心脏，使用Vivo Rationt and In vivo Ratigtion and In vivo Ratigtion and In vivo Ratigtion的培养心脏，心肌细胞肥大。我们在提出的动物和细胞模型以及研究心脏病中线粒体功能的必要技术以及开发新的药理学和有条件策略以进行心脏保护方面的必要技术。该提案的具体目的是：（1）检查后施加后重塑对心力衰竭的进展是否与MPTP开放和线粒体碎片的增加有关； （2）确定MPTP是否由心脏重塑中的AMPK/PPARALPHA途径调节； （3）定义抑制MPTP是否在结构后重塑期间是否具有长期保护作用。拟议的研究将确定特定的线粒体适应和改变，并有助于制定新的治疗策略来治疗心肌梗死后心力衰竭。