The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats.
The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats.
复制标题
异喹啉-磺胺化合物H-1337减轻SU5416/缺氧引起的大鼠肺动脉高压
DOI：
10.3390/cells11010066
复制
发表时间：
2021-12-27
期刊：
影响因子：
6
通讯作者：
Tatsumi K
中科院分区：
文献类型：
--
作者：
Shoji H;Yoshida Y;Sanada TJ;Naito A;Maruyama J;Zhang E;Sumi K;Sakao S;Maruyama K;Hidaka H;Tatsumi K
肺动脉高压（PAH）的特征是肺动脉压升高和右心衰竭。选择性肺血管扩张剂改善了PAH的预后;然而，它们不能逆转肺血管重构。因此，需要寻找新的治疗剂。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）。在此，我们研究了H-1337对由SU 5416和缺氧暴露诱导的实验性PAH中肺动脉高压和肺血管和右心室重构的影响。H-1337和H-1337 M1对ROCK和Akt有抑制作用。H-1337抑制肌球蛋白轻链和mTOR的磷酸化，抑制平滑肌细胞的增殖。H-1337治疗还抑制肺血管中肌球蛋白轻链和mTOR的磷酸化，并降低右心室收缩压和闭塞性肺血管病变的程度。此外，H-1337抑制了右心室肥大的加重。总之，我们的数据表明，用H-1337抑制ROCK和mTOR通路可抑制肺血管重构、肺动脉高压和右心室重构的进展。
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.
登录
查看更多内容
影响因子：
5.6
作者：
Pópulo H;Lopes JM;Soares P
通讯作者：
Soares P
影响因子：
5.4
作者：
Horita H;Furgeson SB;Ostriker A;Olszewski KA;Sullivan T;Villegas LR;Levine M;Parr JE;Cool CD;Nemenoff RA;Weiser-Evans MC
通讯作者：
Weiser-Evans MC
DOI：
10.1165/rcmb.2016-0364oc
发表时间：
2017-11-01
影响因子：
6.4
作者：
Pena, Andressa;Kobir, Ahasanul;Goncharova, Elena A.
通讯作者：
Goncharova, Elena A.
影响因子：
11.4
作者：
Brunn, GJ;Williams, J;Abraham, RT
通讯作者：
Abraham, RT
影响因子：
37.8
作者：
Andersen, Stine;Nielsen-Kudsk, Jens Erik;de Man, Frances S.
通讯作者：
de Man, Frances S.