ClC-3 mediates angiotensin II-induced endothelial dysfunction by inhibiting Akt-Hsp90-eNOS signaling pathway

Endothelial dysfunction is a major driver for hypertension and diabetes. Chloride (Cl^-) is the most abundant anion in vascular endothelial cells (ECs). However, the role of chloride channel or chloride/proton exchanger ClC-3 in the vascular endothelium and its relationship with endothelium-dependent relaxation remains unclear.

This study aims to explore the role and mechanism of ClC-3 in endothelial dysfunction during hypertension, by using primary cultured human umbilical vein endothelial cells (HUVECs) and ClC-3 knockout mice.

We found that AngiotensinII (AngII) treatment significantly upregulated ClC-3 expression and reduced NO levels, while ClC-3 interference increased eNOS phosphorylation. Furthermore, in AngII-infused hypertensive mouse models, ClC-3 knockout significantly increased the phosphorylation level of eNOS and improved vascular relaxation function. In vitro data shows that ClC-3 interacted with eNOS through its oxygenase domain in HUVECs. Moreover, lack of ClC-3 promoted eNOS-Hsp90-Akt complex formation and eNOS disassociation from caveolin-1, and upregulation the phosphorylation of Akt.

Our findings suggest that ClC-3 may serve as an important target for hypertension-related endothelial dysfunction, potentially providing new strategies and interventions for the treatment of hypertension and its complications.