PGC1α 介导的肺动脉高压雌性大鼠和人类中线粒体融合蛋白 2 缺乏。
PGC1α-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension.
机构信息
Section of Cardiology, Department of Medicine, University of Chicago, Chicago, IL, USA.
出版信息
Am J Respir Crit Care Med. 2013 Apr 15;187(8):865-78. doi: 10.1164/rccm.201209-1687OC.
RATIONALE
Pulmonary arterial hypertension (PAH) is a lethal, female-predominant, vascular disease. Pathologic changes in PA smooth muscle cells (PASMC) include excessive proliferation, apoptosis-resistance, and mitochondrial fragmentation. Activation of dynamin-related protein increases mitotic fission and promotes this proliferation-apoptosis imbalance. The contribution of decreased fusion and reduced mitofusin-2 (MFN2) expression to PAH is unknown.
OBJECTIVES
We hypothesize that decreased MFN2 expression promotes mitochondrial fragmentation, increases proliferation, and impairs apoptosis. The role of MFN2's transcriptional coactivator, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), was assessed. MFN2 therapy was tested in PAH PASMC and in models of PAH.
METHODS
Fusion and fission mediators were measured in lungs and PASMC from patients with PAH and female rats with monocrotaline or chronic hypoxia+Sugen-5416 (CH+SU) PAH. The effects of adenoviral mitofusin-2 (Ad-MFN2) overexpression were measured in vitro and in vivo.
MEASUREMENTS AND MAIN RESULTS
In normal PASMC, siMFN2 reduced expression of MFN2 and PGC1α; conversely, siPGC1α reduced PGC1α and MFN2 expression. Both interventions caused mitochondrial fragmentation. siMFN2 increased proliferation. In rodent and human PAH PASMC, MFN2 and PGC1α were decreased and mitochondria were fragmented. Ad-MFN2 increased fusion, reduced proliferation, and increased apoptosis in human PAH and CH+SU. In CH+SU, Ad-MFN2 improved walking distance (381 ± 35 vs. 245 ± 39 m; P < 0.05); decreased pulmonary vascular resistance (0.18 ± 0.02 vs. 0.38 ± 0.14 mm Hg/ml/min; P < 0.05); and decreased PA medial thickness (14.5 ± 0.8 vs. 19 ± 1.7%; P < 0.05). Lung vascularity was increased by MFN2.
CONCLUSIONS
Decreased expression of MFN2 and PGC1α contribute to mitochondrial fragmentation and a proliferation-apoptosis imbalance in human and experimental PAH. Augmenting MFN2 has therapeutic benefit in human and experimental PAH.
背景
肺动脉高压（PAH）是一种致命的、以女性为主的血管疾病。PA 平滑肌细胞（PASMC）的病理变化包括过度增殖、抗凋亡和线粒体碎片化。动力相关蛋白的激活增加有丝分裂分裂，促进这种增殖-凋亡失衡。减少融合和降低线粒体融合蛋白 2（MFN2）表达对 PAH 的贡献尚不清楚。
目的
我们假设 MFN2 表达的降低促进线粒体碎片化，增加增殖，并损害凋亡。评估了过氧化物酶体增殖物激活受体 γ 共激活因子 1-α（PGC1α）作为 MFN2 的转录共激活因子的作用。在 PAH PASMC 和 PAH 模型中测试了 MFN2 治疗。
方法
在 PAH 患者和患有单克隆毒素或慢性低氧+苏根-5416（CH+SU）PAH 的雌性大鼠的肺和 PASMC 中测量融合和裂变介质。在体外和体内测量腺病毒融合蛋白-2（Ad-MFN2）过表达的效果。
测量和主要结果
在正常 PASMC 中，siMFN2 降低 MFN2 和 PGC1α 的表达；相反，siPGC1α 降低 PGC1α 和 MFN2 的表达。这两种干预都导致了线粒体碎片化。siMFN2 增加增殖。在啮齿动物和人类 PAH PASMC 中，MFN2 和 PGC1α 减少，线粒体碎片化。Ad-MFN2 增加融合，减少增殖，增加人类 PAH 和 CH+SU 中的细胞凋亡。在 CH+SU 中，Ad-MFN2 改善了行走距离（381 ± 35 与 245 ± 39 m；P < 0.05）；降低肺动脉阻力（0.18 ± 0.02 与 0.38 ± 0.14 mm Hg/ml/min；P < 0.05）；降低 PA 中层厚度（14.5 ± 0.8 与 19 ± 1.7%；P < 0.05）。MFN2 增加了肺血管密度。
结论
MFN2 和 PGC1α 的表达降低导致人类和实验性 PAH 中的线粒体碎片化和增殖-凋亡失衡。增加 MFN2 对人类和实验性 PAH 具有治疗益处。
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