Department of Pharmacology and Physiology, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
Can J Physiol Pharmacol. 2021 Feb;99(2):237-246. doi: 10.1139/cjpp-2020-0415. Epub 2020 Oct 1.
We earlier showed that angiotensin (Ang) II-induced overexpression of Giα proteins contributes to the hyperproliferation of vascular smooth muscle cells (VSMC). In addition, the implication of the JAK2/STAT3 pathway in Ang II-induced hyperproliferation of VSMC has also been reported. However, the role of the JAK2/STAT3 pathway in Ang II-induced overexpression of Giα proteins and hyperproliferation of VSMC remains unexplored. In the present study, we show that inhibition or knockdown of the JAK2/STAT3 pathway by a specific inhibitor "cucurbitacin I" (CuI) or siRNAs attenuated Ang II-induced overexpression of Giα proteins and hyperproliferation of VSMC. In addition, the enhanced expression of cell cycle proteins induced by Ang II was also attenuated by CuI. Furthermore, Ang II-induced enhanced production of the superoxide anion (O ), HO, and NADPH oxidase activity, as well as the enhanced expression of NADPH oxidase subunits implicated in enhanced expression of Giα proteins and hyperproliferation, were also attenuated by inhibition of the JAK2/STAT3 pathway. On the other hand, Ang II-induced inhibition and augmentation of the levels of nitric oxide and peroxynitrite, respectively, in VSMC were restored to control levels by CuI. In summary, our results demonstrate that Ang II through the JAK2/STAT3 pathway increases nitroxidative stress, which contributes to the overexpression of Giα proteins and cell cycle proteins and the hyperproliferation of VSMC.
我们之前已经表明，血管平滑肌细胞（VSMC）中血管紧张素（Ang）II 诱导的 Giα 蛋白过表达导致过度增殖。此外，JAK2/STAT3 途径在 Ang II 诱导的 VSMC 过度增殖中的作用也已被报道。然而，JAK2/STAT3 途径在 Ang II 诱导的 Giα 蛋白过表达和 VSMC 过度增殖中的作用仍未被探索。在本研究中，我们表明，通过特定抑制剂“苦瓜素 I”（CuI）或 siRNA 抑制或敲低 JAK2/STAT3 途径可减弱 Ang II 诱导的 Giα 蛋白过表达和 VSMC 过度增殖。此外，Ang II 诱导的细胞周期蛋白表达增强也被 CuI 减弱。此外，Ang II 诱导的超氧阴离子（O ）、HO 和 NADPH 氧化酶活性的增强产生，以及 NADPH 氧化酶亚基的增强表达，这些亚基与 Giα 蛋白过表达和过度增殖有关，也被 JAK2/STAT3 途径的抑制所减弱。另一方面，Ang II 诱导的 VSMC 中一氧化氮和过氧亚硝酸盐水平的抑制和增强分别被 CuI 恢复到对照水平。总之，我们的结果表明，Ang II 通过 JAK2/STAT3 途径增加了氧化应激，这导致了 Giα 蛋白和细胞周期蛋白的过表达以及 VSMC 的过度增殖。
