Enhancing Autophagy and Mitochondrial Biogenesis to Mitigate Cardiac Reperfusion Injury

增强自噬和线粒体生物发生以减轻心脏再灌注损伤

• 批准号: 10031893
• 负责人: Min Xie
• 金额: $ 40.22万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10031893
• 关键词: Affect; Autophagocytosis; Biogenesis; Biological Process; Brain; Cardiac; Cardiac Myocytes; Cell Death; Cell Respiration; Clinical; Data; Excision; FDA approved; Genetic; Heart; Histone Deacetylase Inhibitor; Homeostasis; Impairment; Infarction; Ischemia; Kidney; Knowledge; Lead; Mediating; Medicine; Mitochondria; Modeling; Molecular; Mus; Myocardial Infarction; Myocardial Ischemia; PPAR gamma; Parkinson Disease; Pathway interactions; Patients; Peptides; Pharmacologic Substance; Pharmacology; Process; Proteins; Quality Control; Quality of life; Recycling; Regulation; Reperfusion Injury; Reperfusion Therapy; Role; Signal Transduction; Testing; Time; Vorinostat; attenuation; base; cardioprotection; gain of function; genetic manipulation; heart damage; improved; loss of function; mitochondrial autophagy; mouse model; novel therapeutics; overexpression; parkin gene/protein; parkin protein; patient population; small molecule; transcription factor; ubiquitin ligase

PROJECT SUMMARY: In reperfused myocardial infarction (MI), approximately 50% of cell death is due to reperfusion injury, which still lacks clinical therapies. There is an urgent need to fill in this knowledge gap and to develop novel therapies for this. Initial appropriate mitochondrial quality control is critical for cardioprotection following ischemia/reperfusion (I/R). Mitochondrial homeostasis is tightly regulated by two processes: mitophagy (degradation of damaged mitochondria by autophagy) and mitochondrial biogenesis. Autophagy, an evolutionarily conserved process required for cellular constituent recycling (including mitochondria), is impaired during I/R. Mitochondrial biogenesis is regulated in part by peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1). Importantly, mitochondria biogenesis is not increased by I/R injury in the kidney and brain, despite induction of PGC1. These results suggest that impaired autophagy/mitophagy following I/R contributes to the attenuation of mitochondrial biogenesis. Enhancing autophagy and mitochondrial biogenesis simultaneously during I/R may therefore restore mitochondrial homeostasis. Consistent with this, our unpublished data show that specific induction of autophagy with Tat-Beclin peptide at the time of reperfusion reduces infarct size in mice, and augments PGC1 expression and mitochondrial biogenesis (dependent on the autophagy). Similarly, pharmacological activation of autophagy at the time of reperfusion (using the FDA-approved HDAC inhibitor, SAHA) induces autophagy and PGC1 and reduces infarct size >40%. Moreover, SAHA plus PGC1 overexpression further increased mitochondrial biogenesis. Studies in the brain have identified Parkin and PARIS as the regulator of PGC1 expression. To study Parkinson’s disease, mouse models, and small molecules enhancing Parkin activity are available. Hypothesis: Activation of autophagy confers cardioprotection during I/R through the combined removal of damaged mitochondria and subsequent replacement via PGC1-dependent mitochondrial biogenesis, in a Parkin-PARIS dependent manner, and enhancing both processes will afford more effective cardioprotection. Aim 1. To determine whether autophagy is both necessary and sufficient for mitochondrial biogenesis under basal conditions and during cardiac I/R. Aim 2. To define whether autophagy-mediated mitochondrial biogenesis and cardioprotection during I/R are dependent on the Parkin-PARIS-PGC1 signaling axis. Aim 3. To establish whether simultaneous enhancement of autophagy/mitophagy and mitochondrial biogenesis during cardiac I/R will augment cardioprotection. Significance and novelty. This study will determine whether autophagy and PGC1-dependent mitochondrial biogenesis is critical for reperfusion injury. Clinically, inducing autophagy and mitochondrial biogenesis during the reperfusion is pharmaceutically feasible, which may lead to novel therapies for reperfusion injury. 1

在再灌注心肌梗死（MI）中，大约50%的细胞死亡是由于 再灌注损伤，这仍然缺乏临床治疗。迫切需要填补这一知识空白， 开发新的治疗方法最初适当的线粒体质量控制对心脏保护至关重要 缺血/再灌注（I/R）后。线粒体内稳态受到两个过程的严格调节：线粒体自噬 （通过自噬降解受损的线粒体）和线粒体生物发生。自噬 细胞成分（包括线粒体）再循环所需的进化保守过程受损 在I/R期间。线粒体生物合成部分受过氧化物酶体增殖物激活受体γ调节 辅激活因子-1 α（PGC 1 α）。重要的是，肾I/R损伤不会增加线粒体生物合成 和脑，尽管诱导PGC 1 β。这些结果表明，受损的自噬/线粒体自噬 随后的I/R有助于线粒体生物合成的减弱。增强自噬， 因此，在I/R期间同时进行线粒体生物合成可以恢复线粒体内稳态。 与此一致，我们未发表的数据表明，Tat-Beclin肽对自噬的特异性诱导作用， 再灌注时间减少了小鼠的梗死面积，并增加了PGC 1 β表达和线粒体 生物发生（依赖于自噬）。类似地，自噬的药理学激活在 再灌注（使用FDA批准的HDAC抑制剂，SAHA）诱导自噬和PGC 1 β，并减少 梗死面积> 40%。此外，SAHA加PGC 1 β过表达进一步增加线粒体生物合成。 在大脑中的研究已经确定帕金和巴黎作为PGC 1 β表达的调节因子。研究 帕金森氏病、小鼠模型和增强帕金活性的小分子都是可用的。 假设：自噬的激活通过联合清除 受损的线粒体和随后通过PGC 1 β依赖的线粒体生物合成的替代，在一个 Parkin-PARIS依赖的方式，并加强这两个过程将提供更有效的心脏保护。 目标1。为了确定自噬是否是线粒体生物合成的必要和充分条件 在基础条件下和在心脏I/R期间。 目标二。确定I/R期间自噬介导的线粒体生物发生和心脏保护作用是否与心肌缺血/再灌注有关， 依赖于Parkin-PARIS-PGC 1 β信号轴。 目标3。为了确定是否同时增强自噬/线粒体自噬和线粒体 心脏I/R期间的生物合成将增强心脏保护。 意义和新奇。这项研究将确定自噬和PGC 1 β依赖的线粒体 生物发生对再灌注损伤至关重要。在临床上，诱导自噬和线粒体生物合成期间 再灌注在药学上是可行的，这可能导致再灌注损伤的新疗法。 1