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 成年哺乳动物的心脏在受伤后不能替换受损组织。确定新的方法 对于心力衰竭患者来说，促进损伤后心脏组织再生具有显著的治疗潜力。 直到最近，只有在低等脊椎动物中才能观察到损伤后完全的心脏再生。 然而，新生小鼠在出生后短暂的时间内，损伤后再生心脏的能力 揭示心脏再生的进化保守机制有很大的潜力。 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 能量利用的代谢开关，从糖酵解到氧化磷酸化。这种新陈代谢开关导致 线粒体产生的活性氧物种(ROS)显著增加，这会导致 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，以及个体代谢物是否可以调节 ROS的产生和心脏组织的再生仍不清楚。脑缺血患者体内ROS生成增加 组织已被证明是线粒体代谢物积累的结果。 琥珀酸，并抑制琥珀酸脱氢酶(SDH)阻止琥珀酸积累和IS 对缺血/再灌注(IR)损伤中氧化还原损伤的心脏保护作用。因此，我们假设这种变化 在出生后的氧气水平可能触发琥珀酸积累和ROS的产生，这有助于 心肌细胞周期存在于出生后的心脏。我们的初步结果表明，注射 新生小鼠心脏中的琥珀酸可抑制新生心肌细胞的增殖和 再生。相反，出生后通过丙二酸治疗抑制SDH延长了 幼年小鼠心肌细胞的增殖与再生。血管紧张素转换酶抑制剂Atpenin A5的给药 SDH在幼年小鼠体内诱导类似于丙二酸的再生反应，显示SDH的中心作用 抑制损伤后促进心肌细胞的增殖和再生。值得注意的是，丙二酸 心肌梗死后对成年小鼠的治疗可刺激心肌细胞增殖、血管重建，并导致 心肌梗死后心脏结构和功能完全恢复。更重要的是，丙二酸治疗 在心肌梗死后1周，心肌梗死和心功能下降导致心肌梗死 随着时间的推移，心脏功能的再生和恢复。我们最重要的假设是丙二酸盐 通过抑制SDH，代谢将成年哺乳动物的心脏重新编程到再生状态。我们在这方面的目标 建议对丙二酸心肌梗死后再生的细胞和分子机制进行剖析。 治疗和SDH抑制。我们的结果揭示了丙二酸抑制SDH在促进心脏方面的新作用 心肌梗死后的再生，不同于对IR损伤的心脏保护作用。

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.