Department of Physiology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
Department of Physiology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
Biochem Biophys Res Commun. 2021 Jan 1;534:795-801. doi: 10.1016/j.bbrc.2020.10.106. Epub 2020 Nov 5.
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. The in vitro and in vivo effects 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 (IC = 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.
肺动脉高压（PAH）是一种进行性和致命性疾病，其特征是肺动脉的不可逆转重塑。尽管已经开发出几种 PAH 药物，但仍需要其他药物。Rho 激酶（ROCK）参与 PAH 的发病机制，因此，其抑制剂可能预防 PAH 的发展。然而，ROCK 同工型特异性抑制剂治疗 PAH 的治疗益处在很大程度上仍然未知。本文使用特发性肺动脉高压（IPAH）患者和野百合碱（MCT）诱导的肺动脉高压（PH）大鼠的肺动脉平滑肌细胞（PASMC），研究了 ROCK2 特异性抑制剂 KD025 的体外和体内作用。ROCK1 在正常和 IPAH-PASMC 之间的表达相似，而 ROCK2 在 IPAH-PASMC 中的表达明显高于正常-PASMC。KD025 以浓度依赖性方式抑制 IPAH-PASMC 的加速增殖（IC = 289 nM）。ROCK2 的 siRNA 敲低也减少了加速增殖。在 MCT-PH 大鼠中，ROCK2 在 PASMC 中的表达上调。KD025（1mg/kg/天）减轻 MCT-PH 大鼠的右心室收缩压升高。这些结果强烈表明，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 可能是治疗 PAH 的新治疗靶点。
