Metformin Therapy for Ischemic Insult and Reperfusion Injury in Aging

二甲双胍治疗衰老缺血性损伤和再灌注损伤

• 批准号: 10846164
• 负责人: Edward J Lesnefsky
• 金额: $ 38.04万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10846164
• 关键词: 5' -AMP-activated protein kinase; Acceleration; Acute; Adult; Aging; Amobarbital; Attenuated; Autophagocytosis; Biogenesis; Cardiac; Cardiovascular Diseases; Cell Death; Clinical; Complex; Cytoprotection; Development; Dose; Drug Kinetics; Drug usage; Elderly; Electron Transport; Heart; Heart Injuries; Heart Mitochondria; Heart failure; Impairment; In Vitro; Infarction; Injury; Intravenous; Ischemia; Knockout Mice; Mediating; Metabolic; Metformin; Mitochondria; Mus; Myocardial; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Oral; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phenocopy; Phosphotransferases; Production; Recovery; Reperfusion Injury; Reperfusion Therapy; Role; Scaffolding Protein; Signal Transduction; Stress; Testing; Therapeutic; Therapeutic Intervention; Time; adenylate kinase; aged; cardioprotection; clinical translation; heart damage; heart dimension/size; high risk; improved outcome; in vivo; inhibitor; mitochondrial permeability transition pore; mouse model; myocardial injury; older patient; programs; repaired; small molecule; treatment optimization

In aging, myocardial injury is increased during ischemia-reperfusion and accelerates the transition to post-infarction heart failure. In addition, most therapeutic strategies that effectively decrease cardiac injury in younger hearts fail in aged hearts. Thus, it is a critical unmet need to find an effective approach to decrease cardiac injury in the high risk aged heart during myocardial infarctions and their treatment. Metformin is a currently approved drug for the treatment of type II diabetes. We found that metformin is a reversible inhibitor of electron transport chain complex I. Metformin (2 mM) decreased complex I activity in ischemia-damaged heart mitochondria. Administration of metformin (2 mM) acutely during early reperfusion decreased infarct size in both in vitro and in vivo murine models. The protection of metformin was independent of AMPK activation, since cardiac injury was also decreased in the metformin- treated AMPK kinase dead mouse. Thus, we propose to repurpose metformin as a complex I inhibitor to decrease cardiac injury in aged hearts during the acute phase of reperfusion. AMPK is also a critical stress-activated kinase that exerts longer-term cardiac protection during prolonged recovery periods of reperfusion following myocardial infarction. Aging attenuates AMPK activation and subsequently enhances cardiac injury during ischemia and reperfusion. Sestrin2 is a scaffold protein critical to the activation of AMPK. Sestrin2 deficiency in the aging heart leads to decreased AMPK activation and impairs protective autophagy and mitochondrial biogenesis. We hypothesize that metformin treatment will activate AMPK in aged hearts through modulation of sestrin 2 during prolonged reperfusion. Thus, we propose that high dose metformin treatment provides acute protection in aged hearts during early reperfusion by transiently inhibiting complex I and decreasing mitochondrial-driven injury. Modulation of sestrin2-dependent AMPK activation in aged hearts by continued metformin treatment during longer term reperfusion should provide prolonged protection and consolidate the benefit during longer term recovery and decrease the transition to heart failure. Taken together, metformin presents an attractive opportunity to repurpose a currently approved drug for a new use to potentially attenuate both phases of the enhanced injury following a heart attack in the aged heart in order to improve outcomes in the high risk elderly patient.

在衰老过程中，心肌损伤在缺血-再灌注过程中增加，并加速了缺血-再灌注损伤。 转变为梗死后心力衰竭。此外，大多数有效的治疗策略 减少年轻心脏的心脏损伤在老年心脏中失败。因此，这是一个关键的未满足的需要， 寻找一种有效的方法来减少高危老年心脏在 心肌梗塞及其治疗。二甲双胍是目前批准的药物， 治疗II型糖尿病。我们发现二甲双胍是一种可逆的电子抑制剂， 运输链复合体I二甲双胍（2 mM）降低缺血损伤的复合物I的活性， 心脏线粒体在早期再灌注期间急性给予二甲双胍（2 mM） 在体外和体内小鼠模型中均降低了梗死面积。二甲双胍的保护作用 与AMPK激活无关，因为二甲双胍组的心脏损伤也减少了。 处理AMPK激酶死亡小鼠。因此，我们建议将二甲双胍重新用作复合物I， 抑制剂，以减少再灌注急性期老年心脏的心脏损伤。AMPK 也是一种重要的应激激活激酶，在心肌缺血期间发挥长期的心脏保护作用。 心肌梗死后再灌注恢复期延长。老化减弱 AMPK激活并随后增强缺血和再灌注期间的心脏损伤。 Sestrin 2是AMPK活化的关键支架蛋白。衰老中的Sestrin 2缺乏 心脏导致AMPK活化减少，并损害保护性自噬和线粒体 生物起源。我们假设二甲双胍治疗将激活老年心脏中的AMPK， 在延长的再灌注期间sestrin 2的调节。因此，我们建议高剂量 二甲双胍治疗在早期再灌注期间对老年心脏提供急性保护， 瞬时抑制复合物I并减少脑损伤。调制 持续二甲双胍治疗期间老年心脏中sestrin 2依赖性AMPK激活 长期再灌注应提供延长的保护， 更长期的恢复和减少向心力衰竭的转变。总之，二甲双胍 提供了一个有吸引力的机会，将目前批准的药物重新用于新的用途， 潜在地减弱老年人心脏病发作后增强的损伤的两个阶段 心脏，以改善高风险老年患者的结局。