Myocardial Infarction in the Aging Heart: Ischemia-Damaged Mitochondria, Reticulum Stress and the Transition to Heart Failure

在我们的退伍军人群体中，心血管疾病随着年龄的增长而明显增加。在衰老过程中， 心肌损伤在缺血（ISC）-再灌注（REP）期间增加并导致心力衰竭。 电子传递链（ETC）介导老年心脏ISC-REP过程中线粒体驱动的损伤 由于活性氧（ROS）的产生增加和线粒体磷脂的损伤， 心磷脂（CL）。大多数有效减少年轻心脏心脏损伤的治疗策略都失败了， 老年人的心相反，我们发现在REP早期，ETC复合物I的短暂可逆抑制， 减少老年心脏的损伤。在细胞水平上保护的关键机制和目标， 调解ETC驱动的保护仍然是一个关键的悬而未决的问题。 除了线粒体（MITO）损伤外，内质网（ER）应激也有助于心脏 损伤MITO和ER通过共同的与细胞膜相关的结构并置 （MAM）。MAM在MITO和ER之间的钙调节和脂质代谢中起关键作用。 MAM完整性的破坏可能介导ER和MITO之间的病理性“串扰”， 心脏损伤我们发现CL存在于MAM和ER中，其组成不同于MITO。我们 以前的工作表明，MITO中的CL含量减少，并表现出氧化CL含量的增加 在老年心脏中进行ISC-REP。ER是重建/修复受损CL的关键部位。我们 假设CL是MITO和ER之间通过MAM的“串扰”的关键介体， 通过MAM将受损CL运输到ER是在老化心脏中MAM破坏的介质， ISC-REP. E2诱导的ETC缺陷增加ROS的产生。MITO ROS可损伤MAM并激活ER 应激反应我们发现，老化增加心脏ER应激。MAM美安萌拥有独特的优势， MITO和ER的损伤。老年心脏MITO引起的ROS增加可能损害MAM中的CL 激活内质网应激我们将在基线时评估原发性MITO功能障碍的作用， ISC和早期REP对MAM损伤和目标1中的CL修饰。ETC抑制对MAM的保护作用 在ISC-REP期间进行研究（目标1）。 在老年心脏中MAM和ER对ISC-REP的反应尚不清楚（目的2）。急性、短暂 用可逆抑制剂阻断复合物I可减少老年心脏的损伤。我们发现二甲双胍 以剂量依赖性方式抑制复合物I，特别是在ISC损伤的心脏MITO中。接下来，我们展示了 仅在REP下以抑制复合物I的剂量的二甲双胍治疗在24小时后降低了体内梗死面积。 众议员我们推测，在老年心脏中，REP处复合物I的调节将减弱MAM的损伤。 随后ER应激降低，这反过来使功能失调的MITO的产生最小化， 心脏损伤复合物I的部分抑制被研究作为一种新的上游治疗干预， 减轻老年心脏的心脏损伤并使梗死后心力衰竭的发展最小化（目的3）。

Cardiovascular disease increases markedly with advancing age in our Veteran population. In aging, myocardial injury is increased during ischemia (ISC)-reperfusion (REP) and leads to heart failure. Mitochondrial-driven injury during ISC-REP in aged hearts is mediated by the electron transport chain (ETC) due to increased production of reactive oxygen species (ROS) and damage to the mitochondrial phospholipid cardiolipin (CL). Most therapeutic strategies that effectively decrease cardiac injury in younger hearts fail in aged hearts. In contrast, we found that a transient, reversible inhibition of ETC complex I during early REP decreased injury in the aged heart. The key mechanism and target of protection at the cellular level that mediates ETC-driven protection remains a critical unanswered question. In addition to mitochondria (MITO) damage, endoplasmic reticulum (ER) stress contributes to cardiac injury. MITO and ER are juxtaposed through shared structures of mitochondria-associated membranes (MAM). MAM contribute a critical role in calcium regulation and lipid metabolism between MITO and ER. Disruption of MAM integrity likely mediates pathologic “cross talk” between ER and MITO and increases cardiac injury. We found that CL exists in MAM and the ER with a composition distinct from MITO. Our previous work showed that CL content in MITO is decreased and exhibits an increase in oxidized CL content following ISC-REP in the aged heart. ER is a key site for the remodeling/repair of damaged CL. We hypothesize that CL is a key mediator of the “cross talk” between MITO and ER via the MAM, and that trafficking of damaged CL to ER via the MAM is a mediator of MAM disruption in the aged heart during ISC-REP. Age-induced ETC defects increase ROS production. MITO ROS can damage MAM and activate ER stress responses. We found that aging augments cardiac ER stress. MAM are uniquely positioned to sustain damage from both MITO and ER. The increased ROS from aged heart MITO may damage CL in the MAM and activate ER stress. We will evaluate the role of primary MITO dysfunction at baseline and then following ISC and early REP to MAM damage and CL modification in Aim 1. The role of ETC inhibition to protect MAM during ISC-REP is studied (Aim 1). The response of MAM and ER to ISC-REP in the aged heart is unknown (Aim 2). Acute, transient complex I blockade with a reversible inhibitor decreases injury in aged hearts. We found that metformin inhibits complex I in a dose-dependent manner, especially in ISC-damaged heart MITO. Next, we showed that metformin treatment only at REP in doses that inhibit complex I decreases infarct size in vivo following 24 hrs. REP. We hypothesize that modulation of complex I at REP in aged hearts will attenuate damage to the MAM with a subsequent decrease in ER stress that, in turn, minimizes the generation of dysfunctional MITO and cardiac injury. The partial inhibition of complex I is studied as a new upstream therapeutic intervention to attenuate cardiac injury and minimize post-infarction heart failure development in aged hearts (Aim 3).