丙二酸促进成人心肌细胞增殖和心脏再生,Circulation

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丙二酸促进成人心肌细胞增殖和心脏再生
Circulation ( IF 35.5 ) Pub Date : 2021-03-05 , DOI: 10.1161/circulationaha.120.049952
Jiyoung Bae ₁ , Rebecca J Salamon ₁ , Emma B Brandt ₁ , Wyatt G Paltzer ₁ , Ziheng Zhang ₁ , Emily C Britt _{2,

3} , Timothy A Hacker ₄ , Jing Fan _{2,

3} , Ahmed I Mahmoud ₁

Affiliation

背景：新生小鼠心肌细胞经历了从糖酵解到氧化磷酸化的代谢转变，导致活性氧产生显着增加，从而导致 DNA 损伤。这些细胞变化有助于心肌细胞细胞周期的退出和心脏再生能力的丧失。调节这种代谢转换和增加活性氧物质产生的机制相对尚未探索。目前的证据表明，缺血组织中活性氧产生的增加是由于线粒体代谢物琥珀酸在缺血期间通过琥珀酸脱氢酶 (SDH) 积累的结果，并且这种琥珀酸在再灌注时迅速氧化。已证明家族性癌症综合征中的 SDH 突变可促进代谢转变为糖酵解代谢，这表明 SDH 在调节细胞代谢中具有潜在作用。琥珀酸和 SDH 是否调节心肌细胞周期活性和心脏代谢状态尚不清楚。方法：在这里，我们研究了琥珀酸和 SDH 抑制在调节出生后心肌细胞周期活性和心脏再生中的作用。结果：我们的结果表明，注射琥珀酸进入新生小鼠会抑制心肌细胞的增殖和再生。我们的证据还表明，出生后丙二酸治疗对 SDH 的抑制延长了幼年小鼠心肌细胞增殖和再生的窗口。值得注意的是，在心肌梗死损伤后将丙二酸治疗扩展到成年小鼠心脏，通过促进成年心肌细胞增殖和血运重建，在损伤后 4 周内产生强烈的再生反应。我们对丙二酸抑制SDH后的代谢物分析诱导了成人心脏代谢的动态变化。结论：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。这些发现支持一种潜在的重要的人类心力衰竭新治疗方法。我们对丙二酸抑制SDH后的代谢物分析诱导了成人心脏代谢的动态变化。结论：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。这些发现支持一种潜在的重要的人类心力衰竭新治疗方法。我们对丙二酸抑制SDH后的代谢物分析诱导了成人心脏代谢的动态变化。结论：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。这些发现支持一种潜在的重要的人类心力衰竭新治疗方法。

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Malonate Promotes Adult Cardiomyocyte Proliferation and Heart Regeneration

Background:Neonatal mouse cardiomyocytes undergo a metabolic switch from glycolysis to oxidative phosphorylation, which results in a significant increase in reactive oxygen species 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 reactive oxygen species production have been relatively unexplored. Current evidence suggests that elevated reactive oxygen species production in ischemic tissues occurs as a result of accumulation of the mitochondrial metabolite succinate during ischemia via succinate dehydrogenase (SDH), and this succinate is rapidly oxidized at reperfusion. 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.Methods:Here, we investigated the role of succinate and SDH inhibition in regulation of postnatal cardiomyocyte cell cycle activity and heart regeneration.Results:Our results demonstrate that injection of succinate into 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 after myocardial infarction injury results in a robust regenerative response within 4 weeks after injury via promoting adult cardiomyocyte proliferation and revascularization. Our metabolite analysis after SDH inhibition by malonate induces dynamic changes in adult cardiac metabolism.Conclusions: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.

更新日期：2021-03-05

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