November 5, 2024Open Access

Targeting GPR39 in structure-based drug discovery reduces Ang II-induced hypertension

Q: What is the clinical evidence from this study?

Study design: Other. Population: Hypertension (n=10). Intervention: GPR39 knockout and Z1780628919 vs. Wild-type / Vehicle control. Primary outcome: Blood pressure and vascular function (preclinical).

Key Result

Targeting GPR39 via genetic knockout or the small molecule ligand Z1780628919 significantly reduced Angiotensin II-induced hypertension, vascular fibrosis, and endothelial inflammation in preclinical models.

Structured PICO

Population

10 adult patients requiring aortic dissection surgery (5 with primary hypertension and 5 normotensive controls) provided aortic tissue samples for analysis alongside in vivo and in vitro models.

Intervention

GPR39 knockout (in vivo), GPR39 knockdown (in vitro), and small molecule ligand Z1780628919

Comparator

Wild-type mice, saline control, or PBS control

Outcome

Blood pressure (systolic, diastolic, and mean arterial pressure) and vascular endothelial function/injury (fibrosis, inflammation, oxidative stress, apoptosis)surrogate

Targeting GPR39, either through genetic ablation or the small molecule ligand Z1780628919, reduces Ang II-induced hypertension and vascular injury by inhibiting Nlrp3-mediated inflammation and apoptosis.

Limitations

Blood pressure measurement in rodents was performed using a tail-cuff method rather than the gold standard radio telemetry.
In vivo experiments were conducted exclusively on male mice, so potential sex differences in GPR39 function remain unexplored.

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.

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Cite This Study

Hua et al. (Tue,) conducted a other in Hypertension (n=10). GPR39 knockout and Z1780628919 vs. Wild-type / Vehicle control was evaluated on Blood pressure and vascular function (preclinical). Targeting GPR39 via genetic knockout or the small molecule ligand Z1780628919 significantly reduced Angiotensin II-induced hypertension, vascular fibrosis, and endothelial inflammation in preclinical models.

synapsesocial.com/papers/6a1ea83c989adebfe89a6a99 https://doi.org/https://doi.org/10.1038/s42003-024-07132-2

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