Malonate Promotes Adult Cardiomyocyte Proliferation and Heart Regeneration.
Malonate Promotes Adult Cardiomyocyte Proliferation and Heart Regeneration.
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DOI：
10.1161/circulationaha.120.049952
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发表时间：
2021-05-18
期刊：
影响因子：
37.8
通讯作者：
Mahmoud AI
中科院分区：
文献类型：
--
作者：
Bae J;Salamon RJ;Brandt EB;Paltzer WG;Zhang Z;Britt EC;Hacker TA;Fan J;Mahmoud AI
新生小鼠心肌细胞经历从糖酵解到氧化磷酸化的代谢转换，导致活性氧（ROS）的产生显著增加，从而诱导DNA损伤。这些细胞变化导致心肌细胞周期退出和心脏再生能力丧失。调控这种代谢开关和ROS产生增加的机制相对而言尚未被探索。目前的证据表明，缺血组织中ROS的产生升高是由于缺血期间线粒体代谢物琥珀酸通过琥珀酸脱氢酶（SDH）积累，而这种琥珀酸在再灌注时迅速氧化。有趣的是，家族性癌症综合征中的SDH突变已被证明可促进代谢转变为糖酵解代谢，这表明SDH在调节细胞代谢方面具有潜在作用。琥珀酸盐和SDH是否调节心肌细胞周期活性和心脏代谢状态尚不清楚。在这里，我们研究了琥珀酸盐和琥珀酸脱氢酶（SDH）抑制在出生后心肌细胞周期活性和心脏再生中的作用。我们的研究结果表明，在新生小鼠中注射琥珀酸盐可以抑制心肌细胞的增殖和再生。我们的证据还表明，出生后丙二酸处理对SDH的抑制延长了幼年小鼠心肌细胞增殖和再生的窗口期。值得注意的是，将丙二酸盐治疗扩展到心肌梗死损伤后的成年小鼠心脏，通过促进成年心肌细胞增殖和血运重建，在损伤后4周内产生了强大的再生反应。我们的代谢物分析后SDH抑制丙二酸盐诱导成人心脏代谢的动态变化。丙二酸抑制SDH通过代谢重编程促进成人心肌细胞增殖、血运重建和心脏再生。这些发现支持了一种潜在的重要的治疗人类心力衰竭的新方法。
Neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species (ROS) production that induces DNA damage. These cellular changes contribute to cardiomyocyte cell cycle exit and loss of the capacity for cardiac regeneration. The mechanisms that regulate this metabolic switch and the increase in ROS production have been relatively unexplored. Current evidence suggests that elevated ROS production in ischemic tissues occurs due to accumulation of the mitochondrial metabolite succinate during ischemia via succinate dehydrogenase (SDH), and this succinate is rapidly oxidized at reperfusion. Interestingly, mutations in SDH in familial cancer syndromes have been demonstrated to promote a metabolic shift into glycolytic metabolism, suggesting a potential role for SDH in regulating cellular metabolism. Whether succinate and SDH regulate cardiomyocyte cell cycle activity and the cardiac metabolic state remains unclear. Here, we investigated the role of succinate and succinate dehydrogenase (SDH) inhibition in regulation of postnatal cardiomyocyte cell cycle activity and heart regeneration. Our results demonstrate that injection of succinate in neonatal mice results in inhibition of cardiomyocyte proliferation and regeneration. Our evidence also shows that inhibition of SDH by malonate treatment after birth extends the window of cardiomyocyte proliferation and regeneration in juvenile mice. Remarkably, extending malonate treatment to the adult mouse heart following myocardial infarction injury results in a robust regenerative response within 4 weeks following injury via promoting adult cardiomyocyte proliferation and revascularization. Our metabolite analysis following SDH inhibition by malonate induces dynamic changes in adult cardiac metabolism. Inhibition of SDH by malonate promotes adult cardiomyocyte proliferation, revascularization, and heart regeneration via metabolic reprogramming. These findings support a potentially important new therapeutic approach for human heart failure.