TMEM16A inhibits angiotensin II-induced basilar artery smooth muscle cell migration in a WNK1-dependent manner.
TMEM16A inhibits angiotensin II-induced basilar artery smooth muscle cell migration in a WNK1-dependent manner.
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TMEM16A 以 WNK1 依赖性方式抑制血管紧张素 II 诱导的基底动脉平滑肌细胞迁移
DOI：
10.1016/j.apsb.2021.04.013
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Guan Y
中科院分区：
文献类型：
--
作者：
Zheng H;Li X;Zeng X;Huang C;Ma M;Lv X;Zhang Y;Sun L;Wang G;Du Y;Guan Y
血管平滑肌细胞(VSMC)迁移在许多心血管疾病的发病机制中起着关键作用。我们最近发现TMEM16A参与了高血压引起的脑血管重构。然而，目前尚不清楚这种作用是否与VSMC迁移的调节有关。在这里，我们研究了TMEM16A是否以及如何促进基底动脉平滑肌细胞(BASMC)的迁移。我们观察到血管紧张素转换酶促进培养的BASMCs迁移，而TMEM16A的过表达明显抑制了这一作用。TMEM16A过表达可抑制血管紧张素Ⅱ诱导的RhoA/ROCK2的激活以及肌球蛋白轻链磷酸酶(MLCP)和肌球蛋白轻链(MLC20)的磷酸化。但TMEM16A不影响血管紧张素转换酶诱导的肌球蛋白轻链激酶(MLCK)激活。此外，在血管紧张素Ⅱ刺激下，高表达β的BASMC中整合素β3/FAK通路的激活受到抑制，表现为整合素TMEM16A表达减少、FAK磷酸化和F-肌动蛋白重排。与TMEM16A过表达的结果相反，沉默TMEM16A显示出相反的效果。这些体外结果在血管紧张素转换酶诱导高血压期间VSMC特异性TMEM16A转基因小鼠的基底动脉中进一步得到证实。此外，我们还观察到TMEM16A对BASMC迁移的抑制作用是通过降低−敏感的丝氨酸/苏氨酸激酶WNK1的活性来实现的。综上所述，本研究证实TMEM16A可抑制血管紧张素转换酶诱导的BASMC迁移，从而有助于防止血管紧张素转换酶抑制剂引起的高血压时脑血管重构。TMEM16A可能通过抑制WNK1抑制RhoA/ROCK2/MLCP/MLC20和整合素β3/FAK信号通路而发挥这种作用。我们的结果表明，TMEM16A可能成为VSMC迁移相关疾病的新的治疗靶点，如血管重塑。本研究提示，调控TMEM16A的表达和/或活性可能是预防高血压血管重塑的新策略。
Vascular smooth muscle cell (VSMC) migration plays a critical role in the pathogenesis of many cardiovascular diseases. We recently showed that TMEM16A is involved in hypertension-induced cerebrovascular remodeling. However, it is unclear whether this effect is related to the regulation of VSMC migration. Here, we investigated whether and how TMEM16A contributes to migration in basilar artery smooth muscle cells (BASMCs). We observed that AngII increased the migration of cultured BASMCs, which was markedly inhibited by overexpression of TMEM16A. TMEM16A overexpression inhibited AngII-induced RhoA/ROCK2 activation, and myosin light chain phosphatase (MLCP) and myosin light chain (MLC20) phosphorylation. But AngII-induced myosin light chain kinase (MLCK) activation was not affected by TMEM16A. Furthermore, a suppressed activation of integrinβ3/FAK pathway, determined by reduced integrinβ3 expression, FAK phosphorylation and F-actin rearrangement, was observed in TMEM16A-overexpressing BASMCs upon AngII stimulation. Contrary to the results of TMEM16A overexpression, silencing of TMEM16A showed the opposite effects. These in vitro results were further demonstrated in vivo in basilar arteries from VSMC-specific TMEM16A transgenic mice during AngII-induced hypertension. Moreover, we observed that the inhibitory effect of TMEM16A on BASMC migration was mediated by decreasing the activation of WNK1, a Cl−-sensitive serine/threonine kinase. In conclusion, this study demonstrated that TMEM16A suppressed AngII-induced BASMC migration, thus contributing to the protection against cerebrovascular remodeling during AngII-infused hypertension. TMEM16A may exert this effect by suppressing the RhoA/ROCK2/MLCP/MLC20 and integrinβ3/FAK signaling pathways via inhibiting WNK1. Our results suggest that TMEM16A may serve as a novel therapeutic target for VSMC migration-related diseases, such as vascular remodeling. This study suggests that modulation of TMEM16A expression and/or activity might be a novel strategy to prevent hypertension-induced vascular remodeling.
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DOI：
10.1007/s00018-017-2490-4
发表时间：
2017-06
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Finney AC;Stokes KY;Pattillo CB;Orr AW
通讯作者：
Orr AW
DOI：
10.1152/ajpheart.01041.2010
发表时间：
2011-08-01
影响因子：
4.8
作者：
Freed, Darren H.;Chilton, Lisa;Dixon, Ian M. C.
通讯作者：
Dixon, Ian M. C.
影响因子：
64.8
作者：
Yang, Young Duk;Cho, Hawon;Oh, Uhtaek
通讯作者：
Oh, Uhtaek
影响因子：
56.9
作者：
Kimura, K;Ito, M;Kaibuchi, K
通讯作者：
Kaibuchi, K
ClC-3 通道中苏氨酸532 磷酸化是血管紧张素 II 诱导的 Cl(-) 电流和培养血管平滑肌细胞迁移所必需的
影响因子：
7.3
作者：
Ma, Ming-Ming;Lin, Cai-Xia;Guan, Yong-Yuan
通讯作者：
Guan, Yong-Yuan