Deletion of GPR39 Prevents Pulmonary Arterial Hypertension by Attenuating Hypoxia-Induced Aberrant Signaling

Pulmonary arterial hypertension (PAH) is a devastating disease with poor outcome affecting relatively young subjects. The arachidonic acid (AA) metabolite, 15-hydroxyeicosatetraenoic acid (15-HETE), has been implicated in the pathogenesis of hypoxia-induced PAH. We tested the hypothesis that genetic deletion of GPR39, the target receptor for 15-HETE, will attenuate PAH. We subjected wild-type (WT) and GPR39 KO to 4 weeks of hypoxia versus normoxia, after which right ventricular and systemic hemodynamics were measured. Immunohistochemistry of lung was performed for pulmonary arteriolar thickness as well as capillary and pericyte density. Lung tissue was also analyzed for AA and 15-HETE levels as well as signaling events (mRNA and protein levels) downtream of GPR39 activation. Unlike WT mice, GPR39 KO mice did not develop PAH. They also exhibited markedly less pulmonary ateriolar remodeling and greater pulmonary capillary density. mRNA expression of genes in the Gq, Gs and G12/13 pathways were upregulated in the WT mice while GPR39 KO hypoxic showed no change in these genes. WT and not GPR39 KO hypoxic mice exhibited enhanced AKT phosphorylation. Downstream of the phosphatidylinositol 3-kinase-AKT pathway, endothelial nitric oxide synthetase was upregulated in both WT hypoxia and GPR39 KO hypoxia mice, while sonic hedgehog was upregulated only in WT hypoxia mice. We conclude that hypoxia-induced aberrant signaling is markedly attenuated with genetic deletion of GPR39, which is associated with less pulmonary arteriolar remodeling and greater capillary density, thus preventing PAH. These results suggest that pharmacological inhibition of GPR39 may offer a novel treatment for PAH.