Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension.
Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension.
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DOI：
10.1161/circresaha.111.263848
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发表时间：
2012-05-25
影响因子：
20.1
通讯作者：
Archer SL
中科院分区：
文献类型：
--
作者：
Marsboom G;Toth PT;Ryan JJ;Hong Z;Wu X;Fang YH;Thenappan T;Piao L;Zhang HJ;Pogoriler J;Chen Y;Morrow E;Weir EK;Rehman J;Archer SL
肺动脉高压(PAH)是一种致死性综合征，其特征是部分由于肺动脉平滑肌细胞(PASMC)过度增殖而导致的肺血管阻塞。线粒体断裂和缺氧诱导因子-1α(HIF-1α)在肺动脉高压的发生发展中起重要作用，但两者之间的关系和相关性尚不清楚。动力蛋白相关蛋白-1(Drp1)是一种GTP酶，当被磷酸化丝氨酸-616的酶激活时，会导致线粒体分裂。然而，目前尚不清楚线粒体分裂是否是增殖的先决条件。我们假设，DRp1的激活是导致PAH PASMCs线粒体分裂增加的原因，抑制Drp1可能会减缓增殖并具有治疗潜力。实验用人对照组、PAH肺(n=5)和培养的PASMC进行。在大鼠肺切片和PASMC以及由HIF-1α激活剂、钴、慢性缺氧和野百合碱诱导的啮齿动物肺动脉高压模型上进行了平行实验。缺氧诱导因子-1α的激活通过依赖细胞周期蛋白B1/CDK1的丝氨酸-616位DRP1的磷酸化导致线粒体的分裂。在正常的PASMC中，低氧诱导因子-1α被CoCl2或去铁胺激活导致DRP1介导的分裂。抑制缺氧诱导因子-1α可以减少DRP1的激活，防止分裂和减少PASMC的增殖。DRp1抑制剂Mdivi-1和siDRP1都能阻止有丝分裂，并将PAH PASMCs阻滞在G2/M间期。MDVI-1在人PAH PASMC和啮齿动物模型中具有抗增殖作用。Mdivi-1可改善实验性肺动脉高压大鼠的运动能力、右心功能和血流动力学。DRP-1介导的有丝分裂是一种细胞周期检查点，可作为治疗PAH等增殖性疾病的靶点。
Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by pulmonary vascular obstruction due in part to pulmonary artery smooth muscle cell (PASMC) hyperproliferation. Mitochondrial fragmentation and normoxic activation of hypoxia-inducible factor-1α (HIF-1α) have been observed in PAH PASMCs, however their relationship and relevance to the development of PAH is unknown. Dynamin-related protein-1 (DRP1) is a GTPase that, when activated by kinases that phosphorylate Serine-616, causes mitochondrial fission. It is however unknown whether mitochondrial fission is a prerequisite for proliferation. We hypothesize that DRP1 activation is responsible for increased mitochondrial fission in PAH PASMCs and that DRP1 inhibition may slow proliferation and have therapeutic potential. Experiments were conducted using human control and PAH lungs (n=5) and PASMCs in culture. Parallel experiments were performed in rat lung sections and PASMCs and in rodent PAH models induced by the HIF-1α activator, cobalt, chronic hypoxia, and monocrotaline. HIF-1α activation in human PAH leads to mitochondrial fission by cyclin B1/CDK1-dependent phosphorylation of DRP1 at Serine-616. In normal PASMC, HIF-1α activation by CoCl2 or desferrioxamine causes DRP1-mediated fission. HIF-1α inhibition reduces DRP1 activation, prevents fission and reduces PASMC proliferation. Both the DRP1 inhibitor Mdivi-1 and siDRP1 prevent mitotic fission and arrest PAH PASMCs at the G2/M interphase. Mdivi-1 is antiproliferative in human PAH PASMC and in rodent models. Mdivi-1 improves exercise capacity, right ventricular function and hemodynamics in experimental PAH. DRP-1-mediated mitotic fission is a cell cycle checkpoint that can be therapeutically targeted in hyperproliferative disorders such as PAH.