Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Key Laboratory of Drug Monitoring and Control, Drug Intelligence and Forensic Center, Ministry of Public Security, Beijing, China.
Cell Prolif. 2021 Dec;54(12):e13146. doi: 10.1111/cpr.13146. Epub 2021 Nov 1.
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 ) 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.
最近的研究表明 LRRC8A 是体积调节阴离子通道（VRAC）的必需组成部分，该通道调节细胞体积稳态。然而，LRRC8A 依赖性 VRAC 活性在血管平滑肌细胞（VSMCs）中的作用仍缺乏证据，LRRC8A 在 VSMCs 中的相关功能作用仍不清楚。本研究的主要目的是阐明 LRRC8A 在 VSMCs 中的 VRAC 活性中的作用，以及 LRRC8A 在高血压期间脑血管重塑中的功能作用。
使用 siRNA 介导的敲低和腺病毒介导的 LRRC8A 过表达来阐明 LRRC8A 在基底动脉平滑肌细胞（BASMCs）中的 VRAC 活性的电生理特性。使用平滑肌特异性过表达转基因小鼠模型来研究 LRRC8A 在脑血管重塑中的功能作用。
LRRC8A 是 BASMCs 中体积调节氯电流（I ）所必需的。LRRC8A 的过表达诱导了独立于低渗刺激的电压依赖性 Cl 电流。LRRC8A 通过激活 WNK1/PI3K-p85/AKT 轴调节 BASMCs 的增殖。LRRC8A 的平滑肌特异性上调加重了血管紧张素 II 诱导的小鼠脑血管重塑。
LRRC8A 是 VRAC 的必需组成部分，在 BASMCs 受到渗透挑战时，对细胞体积稳态是必需的。LRRC8A 的平滑肌特异性过表达增加了 BASMCs 的增殖，并显著加重了基底动脉重塑，为高血压血管重塑提供了一个潜在的治疗靶点。
