动力相关蛋白1抑制剂Drpitor1a在肺动脉高压中的疗效
Efficacy of Drpitor1a, a Dynamin-Related Protein 1 inhibitor, in Pulmonary Arterial Hypertension.
作者信息
Wu Danchen, Jansen-van Vuuren Ross D, Dasgupta Asish, Al-Qazazi Ruaa, Chen Kuang-Hueih, Martin Ashley, Mewburn Jeffrey D, Alizadeh Elahe, Lima Patricia D A, Jones Oliver, Colpman Pierce, Breault Nolan M, Emon Isaac M, Jedlovčnik Luka, Zhao Yuan Yuan, Wells Michael, Sutendra Gopinath, Archer Stephen L
出版信息
bioRxiv. 2023 Dec 23:2023.12.21.572836. doi: 10.1101/2023.12.21.572836.
RATIONALE
Dynamin-related protein 1 (Drp1), a large GTPase, mediates mitochondrial fission. Increased Drp1-mediated fission permits accelerated mitosis, contributing to hyperproliferation of pulmonary artery smooth muscle cells (PASMC), which characterizes pulmonary arterial hypertension (PAH). We developed a Drp1 inhibitor, Drpitor1a, and tested its ability to regress PAH.
OBJECTIVES
Assess Drpitor1a's efficacy and toxicity in: a)normal and PAH human PASMC (hPASMC); b)normal rats versus rats with established monocrotaline (MCT)-induced PAH.
METHODS
Drpitor1a's effects on recombinant and endogenous Drp1-GTPase activity, mitochondrial fission, and cell proliferation were studied in hPASMCs (normal=3; PAH=5). Drpitor1a's pharmacokinetics and tissue concentrations were measured (n=3 rats/sex). In a pilot study (n=3-4/sex/dose), Drpitor1a (1mg/kg/48-hours, intravenous) reduced adverse PA remodeling only in females. Consequently, we compared Drpitor1a to vehicle in normal (n=6 versus 8) and MCT-PAH (n=9 and 11) females, respectively. Drpitor1a treatment began 17-days post-MCT with echocardiography and cardiac catheterization performed 28-29 days post-MCT.
RESULTS
Drpitor1a inhibited recombinant and endogenous Drp1 GTPase activity, which was increased in PAH hPASMC. Drpitor1a inhibited mitochondrial fission and proliferation and induced apoptosis, in PAH hPASMC but not normal hPASMC. Drpitor1a tissue levels were higher in female versus male RVs. In MCT-PAH females, Drpitor1a regressed PA obstruction, lowered pulmonary vascular resistance, and improved RV function, without hematologic, renal, or hepatic toxicity.
CONCLUSIONS
Drpitor1a inhibits Drp1 GTPase, reduces mitochondrial fission, and inhibits cell proliferation in PAH hPASMC. Drpitor1a caused no toxicity in MCT-PAH and had no significant effect on normal rats or hPASMCs. Drpitor1a is a potential PAH therapeutic which displays an interesting therapeutic sexual dimorphism.
原理
动力相关蛋白1（Drp1）是一种大型GTP酶，介导线粒体分裂。Drp1介导的分裂增加会加速有丝分裂，导致肺动脉平滑肌细胞（PASMC）过度增殖，这是肺动脉高压（PAH）的特征。我们开发了一种Drp1抑制剂Drpitor1a，并测试了其使PAH消退的能力。
目的
评估Drpitor1a在以下方面的疗效和毒性：a）正常和PAH人PASMC（hPASMC）；b）正常大鼠与已建立的野百合碱（MCT）诱导的PAH大鼠。
方法
在hPASMC中研究了Drpitor1a对重组和内源性Drp1 - GTP酶活性、线粒体分裂和细胞增殖的影响（正常=3；PAH = 5）。测量了Drpitor1a的药代动力学和组织浓度（n = 3只大鼠/性别）。在一项初步研究中（n = 3 - 4/性别/剂量），Drpitor1a（1mg/kg/48小时，静脉注射）仅在雌性中减少了不良的肺血管重塑。因此，我们分别在正常雌性（n = 6对8）和MCT - PAH雌性（n = 9和11）中比较了Drpitor1a与赋形剂。Drpitor1a治疗在MCT后17天开始，在MCT后28 - 29天进行超声心动图和心导管检查。
结果
Drpitor1a抑制重组和内源性Drp1 GTP酶活性，PAH hPASMC中的该活性增加。Drpitor1a抑制PAH hPASMC中的线粒体分裂和增殖并诱导细胞凋亡，但对正常hPASMC无此作用。雌性右心室中的Drpitor1a组织水平高于雄性。在MCT - PAH雌性中，Drpitor1a减轻了肺阻塞，降低了肺血管阻力并改善了右心室功能，且无血液学、肾脏或肝脏毒性。
结论
Drpitor1a抑制Drp1 GTP酶，减少线粒体分裂，并抑制PAH hPASMC中的细胞增殖。Drpitor1a在MCT - PAH中未引起毒性，对正常大鼠或hPASMC无显著影响。Drpitor1a是一种潜在的PAH治疗药物，显示出有趣的治疗性别的差异。
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