The Rho kinase 2 (ROCK2)-specific inhibitor KD025 ameliorates the development of pulmonary arterial hypertension
The Rho kinase 2 (ROCK2)-specific inhibitor KD025 ameliorates the development of pulmonary arterial hypertension
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Rho 激酶 2 (ROCK2) 特异性抑制剂 KD025 可改善肺动脉高压的发展
DOI：
10.1016/j.bbrc.2020.10.106
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发表时间：
2021
影响因子：
3.1
通讯作者：
Sato Motohiko
中科院分区：
文献类型：
--
作者：
Yamamura Aya;Nayeem Md Junayed;Sato Motohiko
肺动脉高压（PAH）是一种以肺动脉不可逆重构为特征的进行性致命疾病。虽然已经开发了几种多环芳烃药物，但还需要更多的药物。Rho激酶（ROCKs）参与了PAH的发病机制，因此，它们的抑制剂可能阻止PAH的发展。然而，ROCK异构体特异性抑制剂对多环芳烃的治疗益处仍然很大程度上未知。本文利用特发性肺动脉高压（IPAH）患者和单氯胆碱（MCT）诱导的肺动脉高压（PH）大鼠的肺动脉平滑肌细胞（PASMCs）检测了rock2特异性抑制剂KD025的体外效应。ROCK1在正常-和IPAH-PASMCs中的表达相似，而ROCK2在IPAH-PASMCs中的表达明显高于正常- pasmcs。KD025对IPAH-PASMCs增殖的抑制呈浓度依赖性（IC50= 289 nM）。ROCK2的siRNA敲低也降低了细胞的增殖速度。在MCT-PH大鼠中，PASMCs中ROCK2表达上调。KD025 （1 mg/kg/天）可降低MCT-PH大鼠右心室收缩压升高。这些结果强烈提示，增强的ROCK2信号参与了PAH发展的致病机制，包括PAH患者PASMC增殖加速和血管重塑。因此，ROCK2可能成为治疗多环芳烃的新靶点。
Pulmonary arterial hypertension (PAH) is a progressive and fatal disease that is characterized by the irreversible remodeling of the pulmonary artery. Although several PAH drugs have been developed, additional drugs are needed. Rho kinases (ROCKs) are involved in the pathogenesis of PAH, and thus, their inhibitors may prevent the development of PAH. However, the therapeutic benefits of ROCK isoform-specific inhibitors for PAH remain largely unknown. Thein vitroandin vivoeffects of the ROCK2-specific inhibitor, KD025, were examined herein using pulmonary arterial smooth muscle cells (PASMCs) from idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline (MCT)-induced pulmonary hypertensive (PH) rats. The expression of ROCK1 was similar between normal- and IPAH-PASMCs, whereas that of ROCK2 was markedly higher in IPAH-PASMCs than in normal-PASMCs. KD025 inhibited the accelerated proliferation of IPAH-PASMCs in a concentration-dependent manner (IC50= 289 nM). Accelerated proliferation was also reduced by the siRNA knockdown of ROCK2. In MCT-PH rats, the expression of ROCK2 was up-regulated in PASMCs. Elevated right ventricular systolic pressure in MCT-PH rats was attenuated by KD025 (1 mg/kg/day). These results strongly suggest that enhanced ROCK2 signaling is involved in the pathogenic mechanism underlying the development of PAH, including accelerated PASMC proliferation and vascular remodeling in patients with PAH. Therefore, ROCK2 may be a novel therapeutic target for the treatment of PAH.