Wang Chenjing, Nan Xiaodong, Pei Shuyan, Zhao Yu, Wang Xiaokun, Ma Shijie, Ma Guoyan
Department of Pharmacology, School of Basic Medical Sciences, Northwest Minzu University Health Science Center, Lanzhou, Gansu 730030, P.R. China.
Intensive Care Unit, Gansu Provincial Corps Hospital of Chinese People's Armed Police Force, Lanzhou, Gansu 730050, P.R. China.
Oncol Lett. 2021 Apr;21(4):292. doi: 10.3892/ol.2021.12553. Epub 2021 Feb 17.
Urotensin II (UII), a vital vasoconstrictor peptide, causes an inflammatory response in the pathogenesis of atherosclerosis. Previous studies have reported that the Ras homolog gene family, member A (RhoA)/Rho kinases (ROCK) pathway modulates the inflammatory response of the atherosclerotic process. However, to the best of our knowledge, whether the RhoA/ROCK pathway mediates the inflammatory effect of UII has not been previously elucidated. Salidroside and isorhamnetin are two early developed antioxidant Tibetan drugs, both displaying cardioprotective effects against atherosclerosis. Therefore, the aim of the present study was to investigate the protective effects of salidroside, isorhamnetin or combination of these two drugs on the UII-induced inflammatory response (rats) or [primary vascular smooth muscle cells (VSMCs)], as well as to examine the role of the RhoA/ROCK pathway in these processes. The levels of inflammatory markers were measured via ELISA. The mRNA and protein expression levels of RhoA and ROCK II were detected using reverse transcription-quantitative PCR assay and western blot analysis. It was demonstrated that salidroside, isorhamnetin and both in combination decreased the levels of the serum pro-inflammatory cytokines TNF-α and IL-1β, as well as increased the levels of the anti-inflammatory cytokine IL-10 and macrophage migration inhibitory factor in rats with subacute infusion of UII and in the culture supernatant from primary VSMCs-exposed to UII. Moreover, salidroside, isorhamnetin and both in combination attenuated the mRNA and protein expression levels of RhoA and ROCK II and , at concentrations corresponding to human therapeutic blood plasma concentrations. Thus, these drugs could inhibit the RhoA/ROCK II pathway under UII conditions. The combination of salidroside and isorhamnetin did not display a stronger inhibitory effect on the inflammatory response and the RhoA/ROCK II pathway compared with salidroside and isorhamnetin in isolation. Collectively, the results indicated that salidroside, isorhamnetin and both in combination inhibited the RhoA/ROCK II pathway, which then attenuated the inflammatory response under UII-induced conditions, resulting in cardioprotection in atherosclerosis.
尾加压素 II（UII）是一种重要的血管收缩肽，在动脉粥样硬化的发病机制中会引发炎症反应。先前的研究报道，Ras 同源基因家族成员 A（RhoA）/Rho 激酶（ROCK）信号通路调节动脉粥样硬化进程中的炎症反应。然而，据我们所知，RhoA/ROCK 信号通路是否介导 UII 的炎症效应此前尚未阐明。红景天苷和异鼠李素是两种早期研发的具有抗氧化作用的藏药，二者均对动脉粥样硬化具有心脏保护作用。因此，本研究的目的是探讨红景天苷、异鼠李素或二者联合用药对 UII 诱导的炎症反应（大鼠）或[原代血管平滑肌细胞（VSMC）]的保护作用，并研究 RhoA/ROCK 信号通路在这些过程中的作用。通过酶联免疫吸附测定（ELISA）检测炎症标志物水平。采用逆转录定量聚合酶链反应（RT-qPCR）和蛋白质免疫印迹分析检测 RhoA 和 ROCK II 的 mRNA 和蛋白表达水平。结果表明，红景天苷、异鼠李素及其联合用药可降低亚急性输注 UII 的大鼠血清促炎细胞因子 TNF-α 和 IL-1β 的水平，并提高抗炎细胞因子 IL-10 和巨噬细胞迁移抑制因子的水平，同时也能提高原代 VSMC 暴露于 UII 后的培养上清液中这些因子的水平。此外，红景天苷、异鼠李素及其联合用药在相当于人体治疗血浆浓度的情况下，可降低 RhoA 和 ROCK II 的 mRNA 和蛋白表达水平。因此，这些药物在 UII 条件下可抑制 RhoA/ROCK II 信号通路。与单独使用红景天苷和异鼠李素相比，二者联合用药对炎症反应和 RhoA/ROCK II 信号通路并未表现出更强的抑制作用。总体而言，结果表明红景天苷、异鼠李素及其联合用药可抑制 RhoA/ROCK II 信号通路，进而减轻 UII 诱导条件下的炎症反应，对动脉粥样硬化起到心脏保护作用。
