Targeting Metabolism To Stimulate Adult Heart Regeneration

项目摘要 心血管疾病是目前世界上发病率和死亡率的主要原因。这是由于 成年哺乳动物心脏在受伤后不能替换受损组织。确定新的方法 对于心力衰竭患者具有显著的治疗潜力。 直到最近，损伤后的心脏完全再生仅在低等脊椎动物中观察到。 然而，新生小鼠在出生后短暂的损伤后再生心脏的能力 表明揭示心脏再生的进化保守机制具有巨大的潜力 来治疗人类的心力衰竭从胚胎/新生儿状态到成年状态的转变伴随着 从糖酵解到氧化磷酸化的能量利用的代谢开关。这种代谢转换导致 线粒体中活性氧（ROS）的产生显著增加， 心肌细胞DNA损伤，导致心肌细胞周期退出和内源性心脏功能丧失， 再生潜力是什么调节了这种代谢开关，以及单个代谢物是否可以调节 ROS的产生和心脏组织再生仍然是未知的。缺血性脑损伤中ROS生成增加 已经证明，由于线粒体代谢物的积累， 琥珀酸脱氢酶（SDH）的抑制阻断琥珀酸积累， 在缺血/再灌注（IR）损伤期间保护心脏免受氧化还原损伤。因此，我们假设， 在出生后的氧气水平可能会引发琥珀酸积累和ROS的产生，这有助于 出生后心脏的心肌细胞细胞周期退出。我们的初步结果表明，注射 琥珀酸在新生小鼠心脏中的作用导致新生心肌细胞增殖的抑制， 再生相反，出生后丙二酸治疗对SDH的抑制延长了 幼鼠心肌细胞增殖和再生。Atpenin A5是一种有效的抑制剂， SDH在幼年小鼠中诱导类似于丙二酸的再生反应，证明了SDH的核心作用 抑制促进损伤后心肌细胞增殖和再生。值得注意的是， MI后成年小鼠的治疗刺激心肌细胞增殖、血管再生，并导致 梗死后心脏结构和功能的完全恢复。更重要的是，丙二酸治疗 心肌梗死后1周，心肌梗死和心功能降低导致心肌梗死。 随着时间的推移心脏功能的再生和恢复。我们的假设是丙二酸 通过SDH抑制将成年哺乳动物心脏代谢重编程为再生状态。我们的目标是 一个建议是剖析丙二酸后MI再生的细胞和分子机制 治疗和SDH抑制。我们的研究结果揭示了一个新的作用，SDH抑制丙二酸在促进心脏 心肌梗死后的再生，这是从IR损伤的心脏保护作用不同。

Project Summary Cardiovascular diseases are currently the major cause of morbidity and mortality in the world. This is due to the inability of the adult mammalian heart to replace damaged tissue following injury. Identifying novel approaches towards regenerating heart tissue following injury has significant therapeutic potential for heart failure patients. Until recently, complete heart regeneration following injury has been observed only in lower vertebrates. However, the ability of neonatal mice to regenerate their hearts following injury for a brief window after birth indicates that uncovering the evolutionarily conserved mechanisms of cardiac regeneration has great potential to treat human heart failure. The transition from embryonic/neonatal states to an adult state is accompanied with a metabolic switch for energy utilization from glycolysis to oxidative phosphorylation. This metabolic switch leads to a significant increase in reactive oxygen species (ROS) production from the mitochondria, which causes cardiomyocyte DNA damage and results in cardiomyocyte cell cycle exit and loss of the endogenous cardiac regeneration potential. What regulates this metabolic switch, and whether individual metabolites can regulate ROS production and cardiac tissue regeneration remains unknown. Increased ROS production in ischemic tissues has been demonstrated to occur as a result of the accumulation of the mitochondrial metabolite succinate, and inhibition of succinate dehydrogenase (SDH) blocks succinate accumulation and is cardioprotective against redox insult during ischemia/reperfusion (IR) injury. Thus, we hypothesized that changes in oxygen levels following birth might trigger succinate accumulation and ROS production, which contributes to cardiomyocyte cell-cycle exit in the postnatal heart. Our preliminary results demonstrate that injection of succinate in the neonatal mouse heart results in inhibition of neonatal cardiomyocyte proliferation and regeneration. Conversely, inhibition of SDH by malonate treatment after birth extends the window of cardiomyocyte proliferation and regeneration in juvenile mice. Administration of Atpenin A5, a potent inhibitor of SDH, induces a regenerative response in juvenile mice similar to malonate, demonstrating a central role for SDH inhibition in promoting cardiomyocyte proliferation and regeneration following injury. Remarkably, malonate treatment of adult mice following MI stimulates cardiomyocyte proliferation, revascularization, and results in complete restoration of cardiac structure and function following infarction. More importantly, malonate treatment at 1-week post-MI following the establishment of infarction and reduction of cardiac function results in myocardial regeneration and restoration of cardiac function over time. Our overarching hypothesis is that malonate metabolically reprograms the adult mammalian heart to a regenerative state via SDH inhibition. Our goal in this proposal is to dissect the cellular and molecular mechanisms of post-MI regeneration following malonate treatment and SDH inhibition. Our results reveal a novel role for SDH inhibition by malonate in promoting heart regeneration following myocardial infarction, which is distinct from the cardioprotective role against IR injury.