上海交通大学学报（医学版）2026，Vol.46Issue(3)：291-300,10.DOI:10.3969/j.issn.1674-8115.2026.03.003
成纤维细胞线粒体功能障碍在肺动脉高压中的作用和机制
Role and mechanism of fibroblast mitochondrial dysfunction in pulmonary arterial hypertension
摘要
Abstract
Objective·To preliminarily investigate the role and mechanism of fibroblast mitochondrial dysfunction and its phenotypic transition in pulmonary arterial hypertension(PAH).Methods·A PAH model was established in rats by using monocrotaline(MCT).Rat pulmonary arterial adventitial fibroblasts(RPAAFs)were isolated and stimulated with transforming growth factor β1(TGF-β1)to induce fibroblast-to-myofibroblast transition(FMT).Interventions were performed using the peroxisome proliferator-activated receptor γ coactivator 1-α(Pgc1α)agonist ZLN005 and the mitochondrial uncoupler Fccp.Hemodynamic parameters were measured via right heart catheterization.Vascular remodeling was assessed by using hematoxylin-eosin staining and immunofluorescence staining.Mitochondrial morphology and function were observed by using transmission electron microscopy and live-cell staining(Mitotracker,TMRM,and MitoSOX).The expression levels of Pgc1α,vimentin,and smooth muscle actin α(α-SMA)were detected by Western blotting.The mRNA expression levels of Col1a1 and Col3a1 were measured by qPCR.Results·Four weeks after MCT injection,mitochondria in rat pulmonary arterial adventitial fibroblasts became fragmented with a reduced mean area(P<0.001),and the protein expression level of Pgc1α decreased(P=0.016),promoting the transition of fibroblasts into myofibroblasts.After stimulation with TGF-β1,RPAAFs showed reduced mitochondrial number(P<0.001),decreased membrane potential(P=0.006),increased reactive oxygen species(P<0.001),decreased Pgc1α expression(P=0.006),significantly increased α-SMA protein expression,and increased Col1a1 and Col3a1 mRNA expression(all P<0.001).Fccp treatment similarly reduced mitochondrial membrane potential(P=0.005)and increased α-SMA,Col1a1,and Col3a1 expression(all P<0.001).Pretreatment with ZLN005 upregulated Pgc1α expression(P<0.001),improved TGF-β1-induced mitochondrial dysfunction,and suppressed α-SMA expression(P<0.001)in fibroblasts.In vivo,ZLN005 attenuated pulmonary artery remodeling,reduced perivascular collagen deposition,lowered right ventricular systolic pressure and mean pulmonary arterial pressure(both P<0.001),upregulated tissue Pgc1α expression,and inhibited α-SMA expression(P=0.007).Conclusion·Fibroblast mitochondrial dysfunction promotes FMT and plays an important role in the pathophysiology of PAH.关键词
肺动脉高压/成纤维细胞/线粒体功能障碍/过氧化物酶体增殖物激活受体-γ共激活因子1αKey words
pulmonary arterial hypertension/fibroblasts/mitochondrial dysfunction/Pgc1α分类
医药卫生引用本文复制引用
陈佳钰,张绘莉..成纤维细胞线粒体功能障碍在肺动脉高压中的作用和机制[J].上海交通大学学报（医学版）,2026,46(3):291-300,10.基金项目
上海市自然科学基金(21ZR1438000). Shanghai Natural Science Foundation(21ZR1438000). （21ZR1438000）
