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: 10475290
• 负责人: Edward J Lesnefsky
• 金额: $ 19.05万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475290
• 关键词: 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; clinically translatable; 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-再灌流过程中增加，并加速 过渡到梗死后心力衰竭。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，这是一个关键的未得到满足的需求 寻找减少高危老年心脏损伤的有效途径 心肌梗死及其治疗。二甲双胍目前是一种被批准用于治疗 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。 转运链复合体I二甲双胍(2 MM)降低缺血损伤复合体I的活性 心脏线粒体。再灌流早期急性应用二甲双胍(2 MM) 在体外和体内小鼠模型中均可减少脑梗塞面积。二甲双胍的保护作用 不依赖于AMPK的激活，因为二甲双胍也减少了心脏损伤。 治疗AMPK激酶死亡小鼠。因此，我们建议将二甲双胍重新定位为复合体I 减少老年心脏再灌流急性期心脏损伤的抑制剂。AMPK 也是一种关键的应激激活的激酶，在心脏保护中发挥更长期的作用 心肌梗死后再灌注恢复期延长。衰老会减退 AMPK激活，继而增强缺血和再灌流期间的心脏损伤。 Sestrin2是一种对AMPK激活至关重要的支架蛋白。Sestrin2缺乏在衰老中的作用 心脏导致AMPK活性降低，损害保护性自噬和线粒体 生物发生学。我们推测二甲双胍治疗将激活老年心脏中的AMPK。 Sestrin-2在长时间再灌流中的调节作用。因此，我们建议高剂量 二甲双胍治疗通过以下方式在老年心脏再灌注早期提供急性保护 瞬时抑制复合体I，减少线粒体损伤。调制方式 老年心脏持续二甲双胍治疗后依赖七叶皂苷2的AMPK激活 较长时间的再灌流应提供长期的保护，并巩固在 长期康复，减少向心力衰竭的过渡。加在一起，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用途 潜在地减轻老年人心脏病发作后强化损伤的两个阶段 以改善高危老年患者的预后。