Abstract
The endothelium-dependent vascular injury, a primary pathological feature of angiotensin II (Ang II)-induced hypertension. This study aimed to explore the role and underlying mechanisms of G protein-coupled receptor 39 (GPR39) in the pathogenesis of Ang II-induced hypertension. For in vivo studies, GPR39 knockout (KO) mice (C57BL/6 J, male) were generated and administered Ang II for 4 weeks. GPR39 expression was upregulated in the aorta of hypertensive patients and mice. The ablation of GPR39 mitigated vascular fibrosis, augmented endothelium-dependent vasodilation, and inhibited endothelial inflammation, oxidative stress, and apoptosis in mice. Additionally, GPR39 KO decreased NOD-like receptor protein 3 (Nlrp3) gene expression in Ang II-stimulated endothelial cells. Notably, Nlrp3 activation counteracted the therapeutic benefits of GPR39 KO. We identified the potential ligand of GPR39 using structure-based high throughput virtual screening (HTVS) and validated its antihypertensive function in vitro and in vivo. The small molecule ligand Z1780628919 of GPR39 can also reduce Ang II-induced hypertension and improve vascular function. GPR39 KO and the small molecule ligand Z1780628919 potentially downregulates Nlrp3, thereby mitigating vascular fibrosis, endothelial inflammation, oxidative stress, and apoptosis. This effect contributes to the alleviation of Ang II-induced hypertension and the rectification of vascular dysfunctions. These findings suggest new avenues for therapeutic intervention.