Hu Jiaxin, Singh Prachi, Li Jingrui, Zhang Jing, Li Fei, Zhang Hehe, Xie Jiang
Department of Respiratory and Critical Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA.
Biomedicines. 2023 Aug 23;11(9):2351. doi: 10.3390/biomedicines11092351.
Loss of Smad3 and the consequent activation of myocardin-related transcription factor (MRTF) are associated with vascular pathologies. This study aimed to examine the impact of persistent hypoxia with intermittent aggravation (PI hypoxia) on cellular senescence and pulmonary arterial remodeling mediated by the Smad3/MRTF imbalance. We examined the effects of PI hypoxia on the Smad3/MRTF pathway and cellular senescence using human pulmonary artery endothelial cells (HPAECs) and in vivo studies in rats. The senescent degree was evaluated using β-galactosidase staining, p16 quantitation and the measurement of senescence-associated secretory phenotype. Structural data in the pathological analysis of pulmonary artery remodeling were collected. Compared to the control, HPAECs and pulmonary tissue from rats exposed to PI hypoxia showed a significantly higher senescent degree, lower expression of Smad3, and higher MRTF levels. The overexpression of Smad3 significantly mitigated HPAECs senescence in vitro. Further, treatment with CCG-203971, which inhibits MRTF, increased Smad3 levels and reduced β-galactosidase positive cells in rat lung tissue. This intervention also alleviated PI hypoxia-induced pathological changes, including remodeling indices of pulmonary arterial thickening, muscularization, and collagen formation. In conclusion, imbalanced Smad3/MRTF signaling is linked to PI hypoxia-induced senescence and pulmonary arterial remodeling, making it a potential therapeutic target for patients with sleep apnea and chronic obstructive pulmonary disease.
Smad3缺失以及随之而来的心肌相关转录因子（MRTF）激活与血管病变有关。本研究旨在探讨持续性缺氧伴间歇性加重（PI缺氧）对由Smad3/MRTF失衡介导的细胞衰老和肺动脉重塑的影响。我们使用人肺动脉内皮细胞（HPAECs）以及大鼠体内研究，检测了PI缺氧对Smad3/MRTF通路和细胞衰老的影响。通过β-半乳糖苷酶染色、p16定量以及衰老相关分泌表型的检测来评估衰老程度。收集肺动脉重塑病理分析中的结构数据。与对照组相比，暴露于PI缺氧的大鼠的HPAECs和肺组织显示出显著更高的衰老程度、更低的Smad3表达以及更高的MRTF水平。Smad3的过表达显著减轻了体外HPAECs的衰老。此外，用抑制MRTF的CCG-203971处理可增加大鼠肺组织中Smad3水平并减少β-半乳糖苷酶阳性细胞。该干预还减轻了PI缺氧诱导的病理变化，包括肺动脉增厚、肌化和胶原形成的重塑指数。总之，Smad3/MRTF信号失衡与PI缺氧诱导的衰老和肺动脉重塑有关，使其成为睡眠呼吸暂停和慢性阻塞性肺疾病患者的潜在治疗靶点。
