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显著增加。在衰老过程中， 心肌损伤在缺血(ISC)-再灌注(REP)过程中增加，并导致心力衰竭。 老年心脏ISC-rep过程中线粒体损伤是由电子传递链(ETC)介导的 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损伤的治疗策略都失败了 老旧的心。相反，我们发现，在早期反应中，ETC复合体I的瞬时可逆抑制 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)应激也对心脏 受伤。MITO和ER通过线粒体相关膜的共同结构并列 (妈妈)。MAM在MITO和ER之间的钙调节和脂代谢中起着关键作用。 MAM完整性的破坏可能介导ER和Mito之间的病理性“串扰”并增加 心脏损伤。我们发现在MAM和ER中存在CL，其组成与Mito不同。我们的 前人的工作表明，MITO中的CL含量减少，而氧化的CL含量增加 跟随ISC-Rep在老年的心脏。ER是损伤CL重塑/修复的关键部位。我们 假设CL是Mito和ER之间通过MAM的“串扰”的关键调解人，并且 通过MAM将受损的CL运输到内质网是老年心脏MAM中断的中介 ISC代表。 年龄诱导的ETC缺陷增加了ROS的产生。Mito Ros可以破坏MAM并激活ER 压力反应。我们发现，衰老会增加心脏内质网应激。MAM处于独特的地位，可以维持 水户和急诊室都造成伤害。老年心脏Mito引起的ROS升高可能损害MAM内的CL 激活内质网压力。我们将在基线时评估原发Mito功能障碍的作用，然后进行后续 在AIM中ISC和早期反应对MAM的损伤和CL的修饰1.ETC抑制对MAM的保护作用 在研究ISC-rep期间(目标1)。 老年心脏MAM和ER对ISC-rep的反应尚不清楚(目标2)。急性的，短暂的 使用可逆抑制剂的复合I受体阻滞剂可减少老年心脏的损伤。我们发现二甲双胍 以剂量依赖的方式抑制复合体I，特别是在ISC受损的心脏Mito。接下来，我们展示了 在24小时后，仅在REP剂量下抑制复合体I的二甲双胍治疗可减少活体心肌梗死范围。 代表。我们假设，在老年心脏中调节复合体I将减轻对MAM的损害 随着内质网应激的减少，进而将功能障碍的Mito和 心脏损伤。络合物I的部分抑制作为一种新的上游治疗干预措施被研究 减少老年心脏的心脏损伤，最大限度地减少心梗后心力衰竭的发展(目标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).