Department of Respirology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
Department of Respiratory Medicine, Tokyo Rosai Hospital, Tokyo 143-0013, Japan.
Cells. 2021 Dec 27;11(1):66. doi: 10.3390/cells11010066.
Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and right heart failure. Selective pulmonary vasodilators have improved the prognosis of PAH; however, they are not able to reverse pulmonary vascular remodeling. Therefore, a search for new treatment agents is required. H-1337 is an isoquinoline-sulfonamide compound that inhibits multiple serine/threonine kinases, including Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR). Here, we investigated the effects of H-1337 on pulmonary hypertension and remodeling in the pulmonary vasculature and right ventricle in experimental PAH induced by SU5416 and hypoxia exposure. H-1337 and H-1337M1 exerted inhibitory effects on ROCK and Akt. H-1337 inhibited the phosphorylation of myosin light chain and mTOR and suppressed the proliferation of smooth muscle cells in vitro. H-1337 treatment also suppressed the phosphorylation of myosin light chain and mTOR in the pulmonary vasculature and decreased right ventricular systolic pressure and the extent of occlusive pulmonary vascular lesions. Furthermore, H-1337 suppressed aggravation of right ventricle hypertrophy. In conclusion, our data demonstrated that inhibition of ROCK and mTOR pathways with H-1337 suppressed the progression of pulmonary vascular remodeling, pulmonary hypertension, and right ventricular remodeling.
肺动脉高压（PAH）的特征是肺动脉压升高和右心衰竭。选择性肺动脉扩张剂改善了 PAH 的预后；然而，它们不能逆转肺血管重构。因此，需要寻找新的治疗药物。H-1337 是一种异喹啉-磺酰胺化合物，可抑制多种丝氨酸/苏氨酸激酶，包括 Rho 相关蛋白激酶（ROCK）和哺乳动物雷帕霉素靶蛋白（mTOR）。在这里，我们研究了 H-1337 对 SU5416 诱导的缺氧暴露引起的实验性 PAH 中肺血管和右心室的高血压和重构的影响。H-1337 和 H-1337M1 对 ROCK 和 Akt 具有抑制作用。H-1337 抑制肌球蛋白轻链和 mTOR 的磷酸化，并抑制体外平滑肌细胞的增殖。H-1337 治疗还抑制了肺血管中肌球蛋白轻链和 mTOR 的磷酸化，降低了右心室收缩压和闭塞性肺血管病变的程度。此外，H-1337 抑制了右心室肥厚的加重。总之，我们的数据表明，用 H-1337 抑制 ROCK 和 mTOR 通路抑制了肺血管重构、高血压和右心室重构的进展。
