BACKGROUND Drp1 (dynamin-related protein 1), a large GTPase, mediates the increased mitochondrial fission, which contributes to hyperproliferation of pulmonary artery smooth muscle cells in pulmonary arterial hypertension (PAH). We developed a potent Drp1 GTPase inhibitor, Drpitor1a, but its specificity, pharmacokinetics, and efficacy in PAH are unknown. METHODS Drpitor1a's ability to inhibit recombinant and endogenous Drp1 GTPase was assessed. Drpitor1a's effects on fission were studied in control and PAH human pulmonary artery smooth muscle cells (hPASMC) and blood outgrowth endothelial cells (BOEC). Cell proliferation and apoptosis were studied in hPASMC. Pharmacokinetics and tissue concentrations were measured following intravenous and oral drug administration. Drpitor1a's efficacy in regressing monocrotaline-PAH was assessed in rats. In a pilot study, Drpitor1a reduced PA remodeling only in females. Subsequently, we compared Drpitor1a to vehicles in control and monocrotaline-PAH females. RESULTS Drp1 GTPase activity was increased in PAH hPASMC. Drpitor1a inhibited the GTPase activity of recombinant and endogenous Drp1 and reversed the increased fission, seen in PAH hPASMC and PAH BOEC. Drpitor1a inhibited proliferation and induced apoptosis in PAH hPASMC without affecting electron transport chain activity, respiration, fission/fusion mediator expression, or mitochondrial Drp1 translocation. Drpitor1a did not inhibit proliferation or alter mitochondrial dynamics in normal hPASMC. Drpitor1a regressed monocrotaline-PAH without systemic vascular effects or toxicity. CONCLUSIONS Drpitor1a is a specific Drp1 GTPase inhibitor that reduces mitochondrial fission in PAH hPASMC and PAH BOEC. Drpitor1a reduces proliferation and induces apoptosis in PAH hPASMC and regresses monocrotaline-PAH. Drp1 is a therapeutic target in PAH, and Drpitor1a is a potential therapy with an interesting therapeutic sexual dimorphism.

中文翻译：

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新型 Drp1 GTPase 抑制剂 Drpitor1a：治疗肺动脉高压的功效。


背景 Drp1（动力相关蛋白 1）是一种大型 GTP 酶，介导线粒体分裂增加，从而导致肺动脉高压 (PAH) 中肺动脉平滑肌细胞过度增殖。我们开发了一种有效的 Drp1 GTPase 抑制剂 Drpitor1a，但其在 PAH 中的特异性、药代动力学和功效尚不清楚。方法 评估 Drpitor1a 抑制重组和内源性 Drp1 GTPase 的能力。在对照和 PAH 人肺动脉平滑肌细胞 (hPASMC) 和血液生长内皮细胞 (BOEC) 中研究了 Drpitor1a 对裂变的影响。在 hPASMC 中研究细胞增殖和凋亡。静脉内和口服药物给药后测量药代动力学和组织浓度。 Drpitor1a 在消除野百合碱-PAH 方面的功效在大鼠中进行了评估。在一项试点研究中，Drpitor1a 仅减少女性的 PA 重塑。随后，我们将 Drpitor1a 与对照和野百合碱-PAH 雌性中的载体进行了比较。结果 PAH hPASMC 中 Drp1 GTPase 活性增加。 Drpitor1a 抑制重组和内源性 Drp1 的 GTP 酶活性，并逆转 PAH hPASMC 和 PAH BOEC 中增加的裂变。 Drpitor1a 抑制 PAH hPASMC 增殖并诱导细胞凋亡，而不影响电子传递链活性、呼吸、裂变/融合介质表达或线粒体 Drp1 易位。 Drpitor1a 不会抑制正常 hPASMC 中的增殖或改变线粒体动力学。 Drpitor1a 使野百合碱-PAH 消退，且没有全身血管效应或毒性。结论 Drpitor1a 是一种特异性 Drp1 GTPase 抑制剂，可减少 PAH hPASMC 和 PAH BOEC 中的线粒体裂变。 Drpitor1a 可减少 PAH hPASMC 的增殖并诱导细胞凋亡，并使野百合碱-PAH 消退。 Drp1 是 PAH 的治疗靶点，而 Drpitor1a 是一种潜在的疗法，具有有趣的治疗性二态性。