南方医科大学学报

南方医科大学学报 ›› 2022, Vol. 42 ›› Issue (10): 1572-1577.doi: 10.12122/j.issn.1673-4254.2022.10.19

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MAL蛋白调控肺动脉平滑肌细胞增殖与凋亡对肺动脉高压的作用和机制

刘进军，李晴晴，曾超超，王月祥，胡擎天，王洪巨，吴士礼   

  1. 蚌埠医学院第一附属医院心血管科，安徽 蚌埠 233000；蚌埠医学院，安徽 蚌埠 233030
  • 出版日期:2022-10-20 发布日期:2022-10-31

Role of myelin and lymphocyte protein in regulating pulmonary artery smooth muscle cell proliferation and apoptosis in pulmonary hypertension

LIU Jinjun, LI Qingqing, ZENG Chaochao, WANG Yuexiang, HU Qingtian, WANG Hongju, WU Shili   

  1. Department of Cardiology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China; Bengbu Medical College, Bengbu 233030, China
  • Online:2022-10-20 Published:2022-10-31

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摘要： 目的 探讨髓磷脂和淋巴细胞蛋白（MAL）在肺动脉高压（PAH）中的作用和机制。方法 收集PAH患者（PAH组）及同期健康体检者（HC组）各50例，采用ELISA检测各组血浆中MAL蛋白的表达水平；根据超声心动图将PAH患者分为中重度组（n=18）和轻度组（n=32），分析MAL蛋白水平与肺动脉高压疾病程度的关系；采用缺氧诱导的肺动脉平滑肌细胞（PAMSCs）异常增殖的PAH体外模型，体外敲除和过表达mal基因，观察MAL对PAMSCs生长状态、细胞增殖能力、抗饥饿诱导的凋亡能力等的影响；另采用NK-κB信号通路抑制剂，探讨MAL调控PAMSCs增殖和凋亡的可能分子机制。结果 PAH患者血浆中MAL的水平显著高于HC组（P<0.05），且中重度组患者显著高于轻度组患者（P<0.001）；体外研究中，缺氧组PASMCs中MAL的mRNA及蛋白表达水平显著高于常氧组（P<0.05）；抑制MAL可显著抑制缺氧诱导的PAMSCs增殖能力，促进饥饿诱导的PAMSCs凋亡（P<0.05）；机制研究证实，下调mal可抑制NK-κB通路激活参与调控PAMSCs增殖（P<0.05）。结论 PAH患者血浆中高水平MAL与疾病程度正相关，抑制MAL通过靶向NF-κB通路抑制PAMSCs异常增殖并促进其凋亡参与改善PAH血管重塑过程。

关键词: 肺动脉高压；髓磷脂和淋巴细胞蛋白；血管重构；肺动脉平滑肌细胞；NF-κB

Abstract: Objective To investigate the role of myelin and lymphocyte protein (MAL) in pulmonary hypertension (PAH). Methods Blood samples were collected from 50 patients with PAH (PAH group) and 50 healthy individuals for detection of plasma MAL expression using ELISA. According to the echocardiographic findings, the patients were divided into moderate/severe group (n=18) and mild group (n=32), and the correlation between MAL protein level and the severity of PAH was analyzed. In a pulmonary artery smooth muscle cell model of PAH with hypoxia-induced abnormal proliferation, the effects of mal gene knockdown and overexpression on cell growth, proliferation and starvation-induced apoptosis were observed; the changes in NK-κB signaling pathway in the transfected cells were detected to explore the molecular mechanism by which MAL regulates PAMSC proliferation and apoptosis. Results The plasma level of MAL was significantly higher in patients with PAH than in healthy individuals (P<0.05), and the patients with moderate/severe PAH had significantly higher MAL level than those with mild PAH (P<0.001). In PAMSCs, exposure to hypoxia significantly increased the mRNA and protein expression levels of MAL (P<0.05), and MAL knockdown obviously inhibited hypoxia- induced proliferation and promoted starvationinduced apoptosis of the PAMSCs (P<0.05). Knocking down mal significantly inhibited the activation of NK-κB signaling pathway that participated in regulation of PAMSC proliferation (P<0.05). Conclusion The plasma level of MAL is elevated in PAH patients in positive correlation with the disease severity. MAL knockdown inhibits abnormal proliferation and promotes apoptosis of PAMSCs by targeted inhibition of the NF-κB signaling pathway to improve vascular remodeling in PAH.

Key words: pulmonary arterial hypertension; myelin and lymphocyte protein; vascular remodeling; pulmonary artery smooth muscle cells; nuclear factor-κB