Xu Wenjing, Wu Yichen, Mao Ruiqi, Jia Yujie, Jiang Hao, Zhang Fengxiao, Huang Dan, He Ximiao, Wang Cheng, Huang Kai
Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Exp Mol Med. 2025 Aug 1. doi: 10.1038/s12276-025-01501-5.
Smooth muscle cells are remarkably plastic. Their reversible differentiation is required for growth and wound healing but also contributes to pathologies such as atherosclerosis and restenosis. Here we demonstrate the role of poly(ADP-ribose) polymerase 1 (PARP1) as a critical master regulator of vascular smooth muscle cells (VSMC) plasticity. A robust activation of PARP1 in VSMCs was observed in artery stenosis and atherosclerotic plaques of rodents and human. Inhibition or deletion of PARP1 suppressed the VSMC phenotype switch in vivo and in vitro. Further analysis identified myocardin and myocardin-associated serum response factor as substrates of PARP1-mediated poly(ADP-ribosyl)ation reaction. Poly(ADP-ribosyl)ation of myocardin and serum response factor dissociated the complex from CArG motif in the target promoter and then transcriptionally suppressed contractile protein expression. Moreover, we demonstrated that c-Jun mediated the stimulation of VSMC proliferation and migration by PARP1. Notably, interaction with myocardin is an important mechanism repressing c-Jun transcriptional activity in VSMCs. Poly(ADP-ribosyl)ation of myocardin and c-Jun disrupted myocardin-c-Jun interaction and abolished this repression to promote c-Jun transactivation and target gene expression, thus stimulating VSMC proliferation and migration. Our data reveal that activation of PARP1 not only suppresses contractile status but also promotes the synthetic proliferative phenotype of VSMCs, indicating a pivotal role for PARP1 in determining the phenotype of VSMCs. Targeting PARP1 may hold therapeutic potential for vascular pathologies.
平滑肌细胞具有显著的可塑性。它们的可逆分化对于生长和伤口愈合是必需的，但也会导致动脉粥样硬化和再狭窄等病理状况。在此，我们证明了聚（ADP - 核糖）聚合酶1（PARP1）作为血管平滑肌细胞（VSMC）可塑性的关键主调节因子的作用。在啮齿动物和人类的动脉狭窄及动脉粥样硬化斑块中观察到VSMC中PARP1的强烈激活。PARP1的抑制或缺失在体内和体外均抑制了VSMC表型转换。进一步分析确定心肌素和心肌素相关血清反应因子是PARP1介导的聚（ADP - 核糖基）化反应的底物。心肌素和血清反应因子的聚（ADP - 核糖基）化使该复合物从靶启动子中的CArG基序解离，进而转录抑制收缩蛋白表达。此外，我们证明c - Jun介导了PARP1对VSMC增殖和迁移的刺激作用。值得注意的是，与心肌素的相互作用是在VSMC中抑制c - Jun转录活性的重要机制。心肌素和c - Jun的聚（ADP - 核糖基）化破坏了心肌素 - c - Jun相互作用并消除了这种抑制作用，从而促进c - Jun反式激活和靶基因表达，进而刺激VSMC增殖和迁移。我们的数据表明，PARP1的激活不仅抑制收缩状态，还促进VSMC的合成增殖表型，表明PARP1在决定VSMC表型方面起关键作用。靶向PARP1可能对血管疾病具有治疗潜力。
