Metformin Therapy for Ischemic Insult and Reperfusion Injury in Aging

在衰老过程中，缺血再灌注过程中心肌损伤加剧，并加速心肌损伤 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和老年心脏的衰竭。因此，这是一个未满足的关键需求 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用于治疗以下疾病的药物 II型糖尿病的治疗。我们发现二甲双胍是一种可逆的电子抑制剂 转运链复合物 I。二甲双胍 (2 mM) 降低缺血损伤中复合物 I 的活性 心脏线粒体。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，梗塞面积均减少。二甲双胍的保护 与 AMPK 激活无关，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用作复合物 I 抑制剂可减少老年心脏再灌注急性期的心脏损伤。 AMPK 也是一种关键的应激激活激酶，在应激过程中发挥长期心脏保护作用 心肌梗塞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。 Sestrin2 是一种对于 AMPK 激活至关重要的支架蛋白。衰老过程中 Sestrin2 缺乏 心脏导致 AMPK 激活减少并损害保护性自噬和线粒体 生物发生。我们假设二甲双胍治疗将通过以下方式激活老年心脏中的 AMPK 长期再灌注过程中 sestrin 2 的调节。因此，我们建议高剂量 二甲双胍治疗可在早期再灌注期间为老年心脏提供急性保护 暂时抑制复合物 I 并减少线粒体驱动的损伤。调制 持续二甲双胍治疗对老年心脏中sestrin2依赖性AMPK的激活作用 长期再灌注应提供长期保护并巩固治疗期间的益处 长期恢复并减少向心力衰竭的转变。综合起来，二甲双胍 提供了一个有吸引力的机会，可以将目前批准的药物重新用于新用途 可能减轻老年人心脏病发作后增强损伤的两个阶段 心脏，以改善高危老年患者的预后。

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.