Liu Weijing, Feng Jie, Zhang Yuan, Hao Yanyan, Zhong Jiajun, Liu Xinchang, Cai Dongcheng, Liu Haorui, Bai Lina, Hu Miaoqing, Lian Hong, Nie Yu, Chen Houzao, Wang Yuyao
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan, China.
J Cell Mol Med. 2025 Aug;29(16):e70741. doi: 10.1111/jcmm.70741.
The mammalian heart exhibits transient but remarkable regenerative capacity during the early postnatal period, after which most cardiomyocytes exit the cell cycle. While the sirtuin family is well-established as regulators of cell cycle progression, its specific role in cardiomyocyte proliferation and cardiac regeneration remains unclear. In this study, we found that Sirt4 expression increased during postnatal heart development. Adenovirus-mediated Sirt4 overexpression in vitro inhibited cardiomyocyte proliferation by inducing oxidative DNA damage. Moreover, cardiomyocyte-specific Sirt4 overexpression in vivo suppressed cardiomyocyte proliferation and impaired neonatal heart regeneration. Using Sirt4-knockout mice, we found that Sirt4 deficiency promoted cardiomyocyte proliferation and extended the heart regeneration window. Furthermore, Sirt4 deficiency improved cardiac function and reduced myocardial fibrosis after ischaemia-reperfusion injury in adult mice. These findings establish Sirt4 as a critical regulator of cardiomyocyte proliferation and cardiac repair, suggesting that targeted Sirt4 inhibition may represent a promising therapeutic strategy for ischaemic heart diseases.
哺乳动物心脏在出生后早期表现出短暂但显著的再生能力，在此之后，大多数心肌细胞退出细胞周期。虽然沉默调节蛋白家族作为细胞周期进程的调节因子已被充分确立，但其在心肌细胞增殖和心脏再生中的具体作用仍不清楚。在本研究中，我们发现Sirt4表达在出生后心脏发育过程中增加。腺病毒介导的Sirt4体外过表达通过诱导氧化性DNA损伤抑制心肌细胞增殖。此外，体内心肌细胞特异性Sirt4过表达抑制心肌细胞增殖并损害新生心脏再生。使用Sirt4基因敲除小鼠，我们发现Sirt4缺乏促进心肌细胞增殖并延长心脏再生窗口。此外，Sirt4缺乏改善成年小鼠缺血再灌注损伤后的心脏功能并减少心肌纤维化。这些发现确立了Sirt4作为心肌细胞增殖和心脏修复的关键调节因子，表明靶向抑制Sirt4可能代表一种有前景的缺血性心脏病治疗策略。
