目的·初步探究成纤维细胞线粒体功能障碍及其表型转化在肺动脉高压（pulmonary arterial hypertension，PAH）中的作用和机制。方法·采用野百合碱（monocrotaline，MCT）构建大鼠PAH模型。提取大鼠肺动脉外膜成纤维细胞（rat pulmonary arterial adventitial fibroblasts，RPAAFs），予以转化生长因子β1（transforming growth factor β1，TGF-β1）刺激构建成纤维细胞-肌成纤维细胞转化细胞模型。应用过氧化物酶体增殖物激活受体-γ共激活因子1α（peroxisome proliferator-activated receptor γ coactivator 1-α，Pgc1α）激动剂ZLN005以及线粒体质子载体解偶联剂Fccp进行干预。通过右心导管检测血流动力学指标，苏木精-伊红染色、免疫荧光染色评估肺血管重构情况。透射电镜和Mitotracker、TMRM和MitoSOX活细胞染色观察线粒体形态和功能。蛋白质印迹法检测Pgc1α、波形蛋白（vimentin）以及平滑肌肌动蛋白α（smooth muscle actin α，α-SMA）的表达水平，实时荧光定量PCR检测胶原蛋白Ⅰ型α1链（collagen type Ⅰ α 1，Col1a1）以及胶原蛋白Ⅲ型α1链（collagen type Ⅲ α 1，Col3a1）的mRNA表达水平。结果·MCT注射4周后，RPAAFs内线粒体碎片化，线粒体平均面积下降（P<0.001），Pgc1α蛋白的表达水平降低（P=0.016），促进成纤维细胞向肌成纤维细胞的转化。RPAAFs予以TGF-β1刺激后，细胞内线粒体数量减少（P<0.001）、膜电位降低（P=0.006）、活性氧升高（P<0.001），Pgc1α表达降低（P=0.006），α-SMA、Col1a1以及Col3a1表达显著升高（P=0.006）。RPAAFs给予Fccp刺激后，线粒体膜电位显著下降（P=0.005），α-SMA、Col1a1以及Col3a1表达同样显著升高（均P<0.001）。ZLN005预处理则上调Pgc1α的表达（P<0.001），改善TGF-β1诱导的线粒体功能障碍，并抑制TGF-β1诱导的成纤维细胞α-SMA的表达（P<0.001）。此外，ZLN005干预还可改善PAH大鼠的肺动脉重构，减轻血管周围胶原沉积，降低右心室收缩压和平均肺动脉压（均P<0.001），同时上调组织中Pgc1α表达并抑制α-SMA的表达（P=0.007）。结论·成纤维细胞线粒体功能障碍，促进成纤维细胞-肌成纤维细胞转化，在PAH的病理生理机制中发挥了重要作用。

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.