The Development of Novel Acute Myocardial Infarction Therapeutics Using Metabolomics and High-Throughput Screening

摘要 缺血再灌注损伤是急性心肌梗死的基础病理。矛盾的是， 目前的急性心肌梗死治疗的共同目标是促进再灌注，并在这样做的过程中，触发导致 致细胞死亡。因此，需要新的治疗方法来限制再灌注所致的损伤。 再灌注损伤的许多病理细胞事件可归因于代谢失调 改建。一种特别感兴趣的代谢物是琥珀酸，它在缺血期间积累。vt.在.的基础上 再灌注时，琥珀酸在电子传递链中被络合物(CX)II消耗，产生反应性 CX I处的氧物种这种反向电子传输(RET)似乎是IR损伤的主要贡献者，并且 最近，预防缺血琥珀酸蓄积被认为是一种新的心脏保护策略。 有趣的是，缺血琥珀酸蓄积似乎是一种进化上保守的现象， 提示在低氧耐受中可能起到了作用。这些明显相互矛盾的观察结果导致了 我们的中心假设的发展：虽然再灌流时琥珀酸氧化对IR损伤是有害的， 琥珀酸蓄积有利于改善线粒体的缺血功能。 在我们的初步数据中，高通量筛查发现去甲尼古丁是一种心脏保护剂。去甲尼古丁 在IR损伤的灌流心脏模型中，改善了IR后的心功能并减少了梗死范围。去甲尼古丁 抑制Cx I活性，减少再灌流时琥珀酸消耗，提示抑制RET可能 这是去甲尼古丁诱导的保护作用的机制。 总体而言，这个项目将调查一个未被开发的心脏新陈代谢领域？？代谢适应。 并利用这些洞察力开发新的急性心肌梗死疗法。

ABSTRACT Ischemia-reperfusion (IR) injury is the underlying pathology of acute myocardial infarction (AMI). Paradoxically, current AMI therapies have the common goal of promoting reperfusion and, in doing so, trigger events that lead to cell death. As a result, there is a need for new therapeutics that limit reperfusion-induced injury. Many of the pathologic cellular events of reperfusion-induced injury can be attributed to maladaptive metabolic remodeling. One particular metabolite of interest is succinate, which accumulates during ischemia. Upon reperfusion, succinate is consumed in the electron transport chain by Complex (Cx) II, generating reactive oxygen species at Cx I. This reverse electron transport (RET) appears to be a major contributor to IR injury, and recently prevention of ischemic succinate accumulation has been proposed as a novel cardioprotective strategy. Interestingly, ischemic succinate accumulation appears to be an evolutionarily conserved phenomenon, suggesting a potential role in hypoxic tolerance. These apparently contradictory observations led to the development of our central hypothesis: while succinate oxidation at reperfusion is detrimental to IR injury, succinate accumulation is beneficial for ischemic mitochondrial function. In our preliminary data, high-throughput screening identified nornicotine as a cardioprotective agent. Nornicotine improved post-IR cardiac function and reduced infarct size in a perfused heart model of IR injury. Nornicotine inhibited Cx I activity, and reduced succinate consumption at reperfusion, suggesting that inhibition of RET might be the mechanism of nornicotine-induced protection. Overall, this project will investigate an underexplored area of cardiac metabolism – metabolic adaptations throughout ischemia – and use these insights to develop novel AMI therapeutics.