Low Chloride–Regulated ClC-5 Contributes to Arterial Smooth Muscle Cell Proliferation and Cerebrovascular Remodeling. Issue 4 (11th February 2022)

• Record Type: Journal Article
• Authors: Gao, Min; Ma, Ming-Ming; Lu, Feng-Ting; Huang, Cheng-Cui; Sun, Lu; Lv, Xiao-Fei; Zhang, Bin; Wang, Guan-Lei; Guan, Yong-Yuan
• Is Part Of: Hypertension. Volume 79:Issue 4(2022)
• Page Start: e73
• Page End: e85
• Publication Date: 2022-02-11
• Subjects: chloride -- ClC-5 -- hypertension -- vascular remodeling; Hypertension -- Periodicals; Hypertension -- Treatment -- Periodicals; 616.132005
• DOI: 10.1161/HYPERTENSIONAHA.121.18472
• Languages: English
• ISSNs: 0194-911X

Abstract

Abstract : Background: Low serum chloride (Cl − ) level is considered an independent predictor of cardiovascular mortality associated with chronic hypertension. However, the underlying mechanisms are unknown. ClC-5, a member of the Cl − channel family, is sensitive to changes in intracellular and extracellular Cl − concentration and conducts outwardly rectifying Cl − currents. The aims of this study were to determine if ClC-5 is regulated by low extracellular Cl −, clarify its putative roles in hypertension-induced cerebrovascular remodeling, and elucidate the associated underlying mechanisms. Methods: Whole-cell patch technique, intracellular Cl − concentration measurements, flow cytometry, Western blot, Clcn5 knockdown (Clcn5 −/y ), and adenovirus-mediated ClC-5 overexpression mice, 2-kidney, 2-clip, and angiotensin II infusion–induced hypertensive models were used. Results: We found that low extracellular Cl − evoked a ClC-5–dependent Cl − current that was abolished by ClC-5 depletion in basilar artery smooth muscle cells (BASMCs). ClC-5 was upregulated in the arterial tissues of rats and patients with hypertension. Low Cl − –induced current and ClC-5 protein expression positively correlated with basilar artery remodeling during hypertension. ClC-5 knockdown ameliorated hypertension-induced cerebrovascular remodeling and smooth muscle cell proliferation, whereas ClC-5 overexpression mice exhibited the opposite phenotype. ClC-5–dependent Cl − efflux induced by low extracellular Cl − activated WNK1 (lysine-deficient protein kinase 1) which, in turn, activated AKT (protein kinase B), and culminated in BASMC proliferation and vascular remodeling. Conclusions: ClC-5 mediates low extracellular Cl–induced Cl − currents in BASMCs and regulates hypertension-induced cerebrovascular remodeling by promoting BASMC proliferation via the WNK1/AKT signaling pathway.