Metabolic Reprogramming of the Adult heart to a Regenerative State

项目摘要 射血分数降低的心力衰竭是一种发病率和死亡率都很高的主要公共卫生负担。 发现再生心脏组织的新方法对心脏具有巨大的治疗潜力 失败的病人。与低等脊椎动物类似，新生小鼠在短暂的损伤后可以再生它们的心脏 出生后的窗户。值得注意的是，我们最近发现，对线粒体酶琥珀酸的抑制 脱氢酶(SDH)可促进成人心肌梗死(MI)后的心脏再生。我们的结果 与先前的研究不同，这些研究表明SDH抑制氧化还原具有心脏保护作用 缺血/再灌流损伤中的损伤，因为我们证明抑制SDH不能保护心脏 对抗心肌梗死。出生后心脏从糖酵解到脂肪酸氧化的代谢转换 有助于心肌细胞周期的退出和内源性心脏再生潜力的丧失。SDH，也是 被称为线粒体复合体II，在调节细胞新陈代谢中起着中心作用，因为它参与了 三羧酸(TCA)循环和电子传递链(ETC)。我们最近发表的研究报告 丙二酸对成年小鼠心肌梗死后SDH的抑制作用 刺激心肌细胞增殖，血管重建，并导致心脏结构和 脑梗塞后的功能。值得注意的是，我们在SDH抑制后的代谢物分析显示 未受损伤成人心脏的代谢变化。我们的主要假设是SDH代谢抑制 对成人心脏进行重新编程，使其处于再生状态。为了确定SDH在成人心脏再生中的作用，我们将 追求以下目标：1)阐明心肌梗死后再生的代谢和细胞机制 SDH抑制后；2)确定SDH抑制促进心肌梗死后的分子机制 3)丙二酸抑制SDH对心肌再生电位的影响 猪模型中的脑梗塞。我们提议的实验将确定SDH抑制的机制 促进心脏再生，以及建立SDH抑制在大动物中的治疗潜力 表现出与老鼠心脏截然不同的生理特征的心脏。总的来说，我们的结果揭示了一个新的角色 抑制SDH在促进心肌梗死后心脏再生方面的作用，这一建议将产生 重要的结果将导致新的治疗策略，以再生成人心脏梗死后。

Project Summary Heart failure with reduced ejection fraction is a major public health burden with high morbidity and mortality. Identifying novel approaches towards regenerating heart tissue has significant therapeutic potential for heart failure patients. Similar to lower vertebrates, neonatal mice can regenerate their hearts following injury for a brief window after birth. Remarkably, we recently discovered that inhibition of the mitochondrial enzyme succinate dehydrogenase (SDH) can promote adult cardiac regeneration following myocardial infarction (MI). Our results are distinct from the previous studies demonstrating a cardioprotective role for SDH inhibition against the redox insult during ischemia/reperfusion injury, as we demonstrate that SDH inhibition does not protect the heart against MI-induced infarction. The metabolic switch from glycolysis to fatty acid oxidation in the postnatal heart contributes to cardiomyocyte cell cycle exit and loss of endogenous cardiac regeneration potential. SDH, also known as mitochondrial complex II, plays a central role in regulating cellular metabolism as it is involved in both the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC). Our recently published study demonstrates that inhibition of SDH by malonate treatment of adult mice following myocardial infarction stimulates cardiomyocyte proliferation, revascularization, and results in restoration of cardiac structure and function following infarction. Remarkably, our metabolite analysis following SDH inhibition demonstrates dynamic metabolic changes in the uninjured adult heart. Our overarching hypothesis is that SDH inhibition metabolically reprograms the adult heart to a regenerative state. To define the role of SDH in adult heart regeneration, we will pursue the following aims: 1) Elucidate the metabolic and cellular mechanisms underlying post-MI regeneration following SDH inhibition; 2) Define the molecular mechanisms by which SDH inhibition promotes post-MI regeneration; 3) Determine the role of SDH inhibition by malonate on regenerative potential following myocardial infarction in a porcine model. Our proposed experiments will define the mechanisms by which SDH inhibition promotes cardiac regeneration, as well as establish the therapeutic potential of SDH inhibition in large animal hearts which exhibit distinct physiology from the mouse heart. Collectively, our results reveal a novel role for SDH inhibition in promoting heart regeneration following myocardial infarction, and this proposal will generate important results that will lead to novel therapeutic strategies to regenerate the adult heart following infarction.