LRRC8A is essential for volume-regulated anion channel in smooth muscle cells contributing to cerebrovascular remodeling during hypertension.
LRRC8A is essential for volume-regulated anion channel in smooth muscle cells contributing to cerebrovascular remodeling during hypertension.
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DOI：
10.1111/cpr.13146
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发表时间：
2021-12
影响因子：
8.5
通讯作者：
Guan YY
中科院分区：
文献类型：
--
作者：
Li XY;Lv XF;Huang CC;Sun L;Ma MM;Liu C;Guan YY
最近的研究表明，LRRC8A是体积调节阴离子通道(Vrac)的重要组成部分，它调节细胞体积的动态平衡。然而，LRRC8A依赖的vrac活性在血管平滑肌细胞(VSMCs)中的作用仍缺乏证据，LRRC8A在VSMCs中的相关功能仍不清楚。本研究的主要目的是阐明LRRC8A在VSMC vrac活性中的作用，以及LRRC8A在高血压时脑血管重构中的作用。采用siRNA介导的LRRC8A基因敲除和腺病毒介导的LRRC8A过表达研究LRRC8A在基底动脉平滑肌细胞(BASMCs)中的电生理特性。采用平滑肌特异性过表达转基因小鼠模型，研究LRRC8A在脑血管重塑中的功能作用。LRRC8A对BASMCs的容量调节性氯电流(ICl，Vol)是必需的。LRRC8A的过表达不依赖于低张刺激而产生电压依赖性的CL-−电流。LRRC8A通过激活WNK1/PI3K-P85/AKT轴调控BASMCs增殖。平滑肌特异性上调LRRC8A加重血管紧张素II诱导的小鼠脑血管重构。LRRC8A是vrac的重要组成部分，是BASMCs在渗透胁迫过程中维持细胞体积稳态所必需的。平滑肌特异性过表达LRRC8A可促进BASMCs增殖，显著加重基底动脉重塑，为高血压血管重塑提供了潜在的治疗靶点。LRRC8A在脑血管重塑中的作用示意图。LRRC8A是BASMC中vrac的重要组成部分。在高血压发作时，激活的LRRC8A通道介导的-C1AK1外流增加−的磷酸化，进而触发AKT的磷酸化，促进BASMC的增殖，最终加剧高血压引起的脑血管重构。
Recent studies revealed LRRC8A to be an essential component of volume‐regulated anion channel (VRAC), which regulates cellular volume homeostasis. However, evidence for the contribution of LRRC8A‐dependent VRAC activity in vascular smooth muscle cells (VSMCs) is still lacking, and the relevant functional role of LRRC8A in VSMCs remains unknown. The primary goal of this study was to elucidate the role of LRRC8A in VRAC activity in VSMCs and the functional role of LRRC8A in cerebrovascular remodeling during hypertension. siRNA‐mediated knockdown and adenovirus‐mediated overexpression of LRRC8A were used to elucidate the electrophysiological properties of LRRC8A in basilar smooth muscle cells (BASMCs). A smooth muscle–specific overexpressing transgenic mouse model was used to investigate the functional role of LRRC8A in cerebrovascular remodeling. LRRC8A is essential for volume‐regulated chloride current (I Cl, Vol) in BASMCs. Overexpression of LRRC8A induced a voltage‐dependent Cl− current independently of hypotonic stimulation. LRRC8A regulated BASMCs proliferation through activation of WNK1/PI3K‐p85/AKT axis. Smooth muscle‐specific upregulation of LRRC8A aggravated Angiotensin II‐induced cerebrovascular remodeling in mice. LRRC8A is an essential component of VRAC and is required for cell volume homeostasis during osmotic challenge in BASMCs. Smooth muscle specific overexpression of LRRC8A increases BASMCs proliferation and substantially aggravates basilar artery remodeling, revealing a potential therapeutic target for vascular remodeling in hypertension. The schematic diagram for LRRC8A role in cerebrovascular remodeling. LRRC8A is an essential component of VRAC in BASMCs. During the challenge of hypertension, the activated LRRC8A channel‐mediated‐Cl− efflux increases WNK1 phosphorylation, which in turn triggers AKT phosphorylation and promotes BASMCs proliferation, eventually exacerbates hypertension‐induced cerebrovascular vascular remodeling.
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影响因子：
64.8
作者：
Duan, D;Winter, C;Horowitz, B
通讯作者：
Horowitz, B
影响因子：
4.5
作者：
Schneider, Linda;Klausen, Thomas K.;Schwab, Albrecht
通讯作者：
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影响因子：
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作者：
Klausen, Thomas Kjaer;Hougaard, Charlotte;Pedersen, Stine F.
通讯作者：
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Swell1是一种质膜蛋白，是体积调节阴离子通道的重要组成部分。
影响因子：
64.5
作者：
Qiu Z;Dubin AE;Mathur J;Tu B;Reddy K;Miraglia LJ;Reinhardt J;Orth AP;Patapoutian A
通讯作者：
Patapoutian A
影响因子：
64.8
作者：
Deneka, Dawid;Sawicka, Marta;Dutzler, Raimund
通讯作者：
Dutzler, Raimund