Centre for Cardiovascular Physiology and Pharmacology, Institute of Cardiovascular Science, University College London, London, United Kingdom; Centre for Rheumatology, Division of Medicine, University College London, London, United Kingdom.
Centre for Cardiovascular Physiology and Pharmacology, Institute of Cardiovascular Science, University College London, London, United Kingdom.
Vascul Pharmacol. 2023 Aug;151:107194. doi: 10.1016/j.vph.2023.107194. Epub 2023 Jul 11.
Pulmonary arterial hypertension (PAH) is a rare cardiopulmonary disorder, involving the remodelling of the small pulmonary arteries. Underlying this remodelling is the hyper-proliferation of pulmonary arterial smooth muscle cells within the medial layers of these arteries and their encroachment on the lumen. Previous studies have demonstrated an association between excessive mitochondrial fragmentation, a consequence of increased expression and post-translational activation of the mitochondrial fission protein dynamin-related protein 1 (DRP1), and pathological proliferation in PASMCs derived from PAH patients. However, the impact of prostacyclin mimetics, widely used in the treatment of PAH, on this pathological mitochondrial fragmentation remains unexplored. We hypothesise that these agents, which are known to attenuate the proliferative phenotype of PAH PASMCs, do so in part by inhibiting mitochondrial fragmentation. In this study, we confirmed the previously reported increase in DRP1-mediated mitochondrial hyper-fragmentation in PAH PASMCs. We then showed that the prostacyclin mimetic treprostinil signals via either the Gs-coupled IP or EP receptor to inhibit mitochondrial fragmentation and the associated hyper-proliferation in a manner analogous to the DRP1 inhibitor Mdivi-1. We also showed that treprostinil recruits either the IP or EP receptor to activate PKA and induce the phosphorylation of DRP1 at the inhibitory residue S637 and inhibit that at the stimulatory residue S616, both of which are suggestive of reduced DRP1 fission activity. Like treprostinil, MRE-269, an IP receptor agonist, and butaprost, an EP receptor agonist, attenuated DRP1-mediated mitochondrial fragmentation through PKA. We conclude that prostacyclin mimetics produce their anti-proliferative effects on PAH PASMCs in part by inhibiting DRP1-mediated mitochondrial fragmentation.
肺动脉高压（PAH）是一种罕见的心肺疾病，涉及小肺动脉的重塑。这种重塑的基础是这些动脉中层的肺动脉平滑肌细胞过度增殖，并侵入管腔。先前的研究表明，线粒体碎片化过度与病理增殖之间存在关联，而线粒体碎片化过度是由于线粒体分裂蛋白 dynamin-related protein 1（DRP1）表达和翻译后激活增加所致，PAH 患者来源的 PASMC 中存在这种关联。然而，广泛用于治疗 PAH 的前列环素类似物对这种病理性线粒体碎片化的影响仍未得到探索。我们假设，这些药物已知可减弱 PAH PASMC 的增殖表型，部分原因是抑制线粒体碎片化。在这项研究中，我们证实了先前报道的 PAH PASMC 中 DRP1 介导的线粒体超碎片化增加。然后我们表明，前列环素类似物 treprostinil 通过 Gs 偶联的 IP 或 EP 受体信号传导，以类似于 DRP1 抑制剂 Mdivi-1 的方式抑制线粒体碎片化和相关的过度增殖。我们还表明，treprostinil 招募 IP 或 EP 受体来激活 PKA，并诱导 DRP1 在抑制性残基 S637 处磷酸化，并抑制在刺激性残基 S616 处磷酸化，这两者都表明 DRP1 分裂活性降低。与 treprostinil 一样，IP 受体激动剂 MRE-269 和 EP 受体激动剂 butaprost 通过 PKA 减轻 DRP1 介导的线粒体碎片化。我们得出结论，前列环素类似物通过抑制 DRP1 介导的线粒体碎片化来产生其对 PAH PASMC 的抗增殖作用。
