CFTR deficiency aggravates Ang II induced vasoconstriction and hypertension by regulating Ca2+ influx and RhoA/Rock pathway in VSMCs
CFTR deficiency aggravates Ang II induced vasoconstriction and hypertension by regulating Ca2+ influx and RhoA/Rock pathway in VSMCs
复制标题
CFTR 缺陷通过调节 VSMC 中的 Ca2+ 内流和 RhoA/Rock 通路，加重 Ang II 诱导的血管收缩和高血压。
DOI：
10.52586/5034
复制
发表时间：
2021-12-30
影响因子：
3.1
通讯作者：
Wang, Guanlei
中科院分区：
文献类型：
--
作者：
Zhao, Liyan;Yuan, Feng;Wang, Guanlei
背景
囊性纤维化跨膜电导调节器（CFTR）与血管张力和血压（BP）有关，然而，其在高血压发生中的作用仍然难以捉摸。在本研究中，我们研究了CFTR对血管紧张素II（Ang II）诱导的高血压的调节作用，并明确了CFTR在血管收缩中的分子作用。
结果
我们发现 Ang II 诱导的高血压动物动脉中 CFTR mRNA 和蛋白表达显着下调。在高血压发生过程中，Cftr-/-小鼠的血压显着高于Cftr+/+小鼠。来自 Cftr-/- 小鼠或与 CFTR 特异性抑制剂 CFTR(inh)-172 预孵育的动脉对 Ang II 表现出更强的收缩反应。在血管平滑肌细胞（VSMC）中，作为VSMC收缩核心的肌球蛋白轻链（MLC）的磷酸化受到CFTR的负调节。此外，CFTR 负向调节 Ang II 响应的细胞内 Ca2+ 浓度 ([Ca2+]i) 升高，而在静息 VSMC 中未观察到任何变化。 Ras 同源家族成员 A/Rho 相关蛋白激酶 (RhoA/Rock) 介导肌球蛋白磷酸酶靶亚基 1 (MYPT1) 的磷酸化，肌球蛋白磷酸酶靶亚基 1 (MYPT1) 是 MLC 磷酸化的调节因子，在静息和 Ang II 刺激的 VSMC 中均受到 CFTR 的负向调节。
结论
本研究表明CFTR是血管收缩和高血压的负调节因子，其潜在机制包含两个可能的途径：（1）在静息VSMC中，CFTR通过RhoA/Rock途径改变MLC磷酸化； (2)在Ang II刺激的VSMC中，其调节作用是由Ca2+内流和RhoA/Rock介导途径共同介导的。
BACKGROUND
Cystic fibrosis transmembrane conductance regulator (CFTR) has been associated with vascular tone and blood pressure (BP), however, its role in the genesis of hypertension remains elusive. In the present study, we investigated the regulating effect of CFTR on angiotensin II (Ang II) -induced hypertension and defined the molecular role of CFTR in vasoconstriction.
RESULTS
We found that CFTR mRNA and protein expression were markedly down-regulated in the arteries from Ang II induced hypertensive animals. During the development of hypertension, BP of Cftr-/- mice was significantly higher than that of Cftr+/+ mice. Arteries from Cftr-/- mice or pre-incubated with CFTR specific inhibitor CFTR(inh)-172 exhibited a greater contractile response to Ang II. In vascular smooth muscle cells (VSMCs), the phosphorylation of myosin light chain (MLC), which is the core of VSMCs contraction, was negatively modulated by CFTR. Furthermore, intracellular Ca2+ concentration ([Ca2+]i) rise in response to Ang II was negatively modulated by CFTR, while no alteration was observed in resting VSMCs. Ras homolog family member A/Rho-associated protein kinase (RhoA/Rock) mediated phosphorylation of myosin phosphatase target subunit 1 (MYPT1), a regulator of MLC phosphorylation, was negatively modulated by CFTR in both resting and Ang II-stimulated VSMCs.
CONCLUSIONS
This study demonstrates that CFTR is a negative regulator of vasoconstriction and hypertension, and the underlying mechanism contains two possible pathways: (1) in resting VSMCs, CFTR altered MLC phosphorylation through RhoA/Rock pathway; (2) in Ang II stimulated VSMCs, the regulating effect was mediated by both Ca2+ influx and RhoA/Rock mediated pathway.
影响因子：
8.2
作者：
Xiang, Sunny Yang;Ye, Linda L.;Duan, Li-lu Marie;Liu, Li-hui;Ge, Zhi-dong;Auchampach, John A.;Gross, Garrett J.;Duan, Dayue Darrel
通讯作者：
Duan, Dayue Darrel