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Hypotonicity-Induced WNK1 Phosphorylation Prevents H2O2-Induced Apoptosis in Vascular Smooth Muscle Cells
Yajuan Zhang1,2, Wei Lin1,3, Fengting Lu1
1Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
Abstract:
Vascular smooth muscle cells (VSMCs) are essential for maintaining arterial wall integrity, with their associated apoptosis critically involved in cardiovascular diseases. Intracellular chloride anion (Cl-) dysregulation is closely linked to apoptosis. However, the underlying mechanism via chloride-sensitive kinases remains unclear. Here, we show that hypotonic stimulation activates volume-regulated chloride channels (VRCCs) and induces the phosphorylation of the chloride-sensitive kinase WNK1. Activated WNK1 protects VSMCs against H2O2-induced apoptosis by maintaining the Bcl-2/Bax balance, preserving mitochondrial membrane potential and inhibiting caspase-9/3 activation. These findings uncover a novel protective role of WNK1 in VRCC-mediated Cl- signalling and provide new perspectives for targeting chloride-sensitive kinases in the treatment of hypertension and related cardiovascular diseases.
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