Lin Qian, Cui Changting, Zhao Ying, Geng Yuefeng, Gao Huimin, Shao Xiaodie, Cheng Ling, Li Haitao, Geng Bin
State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, China.
Department of Emergency Medicine, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Antioxid Redox Signal. 2025 May;42(13-15):655-671. doi: 10.1089/ars.2024.0602. Epub 2024 Sep 30.
Arterial stiffness, a hallmark of vascular aging, significantly contributes to hypertension and impaired organ perfusion. Vascular smooth muscle cell (VSMC) dysfunction, particularly VSMC senescence and its interaction with stiffness, is crucial in the pathogenesis of arterial stiffness. Although hydrogen sulfide (HS) and its key enzyme cystathionine γ-lyase (CSE) are known to play roles in cardiovascular diseases, their effects on arterial stiffness are not well understood. First, we observed a downregulation of CSE/HS in the aortic media during biological aging and angiotensin II (AngII)-induced aging. The VSMC-specific CSE knockout mice were created by loxp-cre (Tagln-cre) system and which exacerbated AngII-induced aortic aging and stiffness and VSMC senescence and stiffness . Conversely, the CSE agonist norswertianolin mitigated these effects. Next, we identified growth arrest-specific 1 (Gas1) as a crucial target of CSE/HS and found it to be a downstream target gene of forkhead box protein M1 (Foxm1). siRNA knockdown Foxm1 increased Gas1 transcription and reduced the protective effects of HS on VSMC senescence and stiffness. Finally, we demonstrated that CSE/HS sulfhydrates Foxm1 at the C210 site, regulating its nuclear translocation and activity, thus reducing VSMC senescence and stiffness. Our findings highlight the protective role of CSE/HS in arterial stiffness, emphasizing the novel contributions of CSE, Gas1, and Foxm1 to VSMC senescence and stiffness. Endogenous CSE/HS in VSMCs reduces VSMC senescence and stiffness, thereby attenuating arterial stiffness and aging, partly through sulfhydration-mediated activation of Foxm1 and subsequent inhibition of Gas1 signaling pathways. 42, 655-671.
动脉僵硬度是血管衰老的一个标志，它在高血压和器官灌注受损的发生发展中起着重要作用。血管平滑肌细胞（VSMC）功能障碍，特别是VSMC衰老及其与僵硬度的相互作用，在动脉僵硬度的发病机制中至关重要。尽管硫化氢（HS）及其关键酶胱硫醚γ-裂解酶（CSE）在心血管疾病中发挥作用，但其对动脉僵硬度的影响尚不清楚。首先，我们观察到在生物衰老和血管紧张素II（AngII）诱导的衰老过程中，主动脉中膜CSE/HS表达下调。通过loxp-cre（Tagln-cre）系统构建了VSMC特异性CSE基因敲除小鼠，其加剧了AngII诱导的主动脉衰老和僵硬度以及VSMC衰老和僵硬度。相反，CSE激动剂异紫堇醇灵减轻了这些影响。接下来，我们确定生长停滞特异性蛋白1（Gas1）是CSE/HS的关键靶点，并发现它是叉头框蛋白M1（Foxm1）的下游靶基因。siRNA敲低Foxm1可增加Gas1转录，并降低HS对VSMC衰老和僵硬度的保护作用。最后，我们证明CSE/HS在C210位点对Foxm1进行巯基化修饰，调节其核转位和活性，从而降低VSMC衰老和僵硬度。我们的研究结果突出了CSE/HS在动脉僵硬度中的保护作用，强调了CSE、Gas1和Foxm1对VSMC衰老和僵硬度的新贡献。VSMC中的内源性CSE/HS可降低VSMC衰老和僵硬度，从而减轻动脉僵硬度和衰老，部分是通过巯基化介导的Foxm1激活以及随后对Gas1信号通路的抑制实现的。42, 655 - 671。
