动力相关蛋白 1 介导线粒体有丝分裂分裂允许血管平滑肌细胞的过度增殖，并为肺动脉高压提供了一个新的治疗靶点。
Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension.
机构信息
Department of Medicine, Section of Cardiology, University of Illinois at Chicago, Chicago, IL, USA.
出版信息
Circ Res. 2012 May 25;110(11):1484-97. doi: 10.1161/CIRCRESAHA.111.263848. Epub 2012 Apr 17.
RATIONALE
Pulmonary arterial hypertension (PAH) is a lethal syndrome characterized by pulmonary vascular obstruction caused, in part, by 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 are 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.
OBJECTIVE
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.
METHODS AND RESULTS
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 PASMCs, HIF-1α activation by CoCl(2) 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 PASMCs and in rodent models. Mdivi-1 improves exercise capacity, right ventricular function, and hemodynamics in experimental PAH.
CONCLUSIONS
DRP-1-mediated mitotic fission is a cell-cycle checkpoint that can be therapeutically targeted in hyperproliferative disorders such as PAH.
背景
肺动脉高压（PAH）是一种致命综合征，其特征为部分由肺动脉平滑肌细胞（PASMC）过度增生引起的肺血管阻塞。在 PAH 的 PASMC 中已经观察到线粒体片段化和缺氧诱导因子-1α（HIF-1α）的氧合激活；然而，它们与 PAH 发展的关系及其相关性尚不清楚。与 GTP 结合的 dynamin 相关蛋白-1（DRP1）是一种 GTPase，当被丝氨酸 616 磷酸化的激酶激活时，会导致线粒体裂变。然而，线粒体裂变是否是增殖的前提尚不清楚。
目的
我们假设 DRP1 的激活是 PAH PASMC 中线粒体裂变增加的原因，并且 DRP1 抑制可能会减缓增殖并具有治疗潜力。
方法和结果
使用人对照和 PAH 肺（n=5）以及培养中的 PASMC 进行了实验。在大鼠肺切片和 PASMC 以及 HIF-1α 激活剂钴、慢性低氧和单核苷酸诱导的啮齿动物 PAH 模型中进行了平行实验。PAH 患者的 HIF-1α 激活导致 cyclin B1/CDK1 依赖性磷酸化 DRP1 丝氨酸 616，从而导致线粒体裂变。在正常的 PASMC 中，CoCl2 或去铁胺激活 HIF-1α 会导致 DRP1 介导的裂变。HIF-1α 抑制可降低 DRP1 的激活，防止裂变并减少 PASMC 的增殖。DRP1 抑制剂 Mdivi-1 和 siDRP1 均可防止有丝分裂裂变，并使 PAH PASMC 停滞在 G2/M 间期。Mdivi-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 PAH 中的运动能力、右心室功能和血液动力学。
结论
DRP-1 介导的有丝分裂裂变是细胞周期检查点，可以在增殖性疾病（如 PAH）中作为治疗靶点。
Zotero 插件