Nitro-oleic acid inhibits angiotensin II-induced hypertension

Rationale: Nitro-oleic acid (OA-NO₂) is a bioactive, nitric-oxide derived fatty acid with physiologically relevant vasculoprotective properties in vivo. OA-NO₂ exerts cell signaling actions as a result of its strong electrophilic nature and mediates pleiotropic cell responses in the vasculature. Objective: The present study sought to investigate the protective role of OA-NO₂ in angiotensin (Ang) II-induced hypertension. Methods and Results: We show that systemic administration of OA-NO₂ results in a sustained reduction of Ang II-induced hypertension in mice and exerts a significant blood pressure lowering effect on preexisting hypertension established by Ang II infusion. OA-NO₂ significantly inhibits Ang II contractile response as compared to oleic acid (OA) in mesenteric vessels. The improved vasoconstriction is specific for the Ang II type 1 receptor (A_T1R)-mediated signaling because vascular contraction by other G-protein-coupled receptors is not altered in response to OA-NO₂ treatment. From the mechanistic viewpoint, OA-NO₂ lowers Ang II-induced hypertension independently of peroxisome proliferation-activated receptor (PPAR)γ activation. Rather, OA-NO ₂, but not OA, specifically binds to the AT1R, reduces heterotrimeric G-protein coupling, and inhibits IP3 (inositol-1,4,5-trisphosphate) and calcium mobilization, without inhibiting Ang II binding to the receptor. Conclusions: These results demonstrate that OA-NO₂ diminishes the pressor response to Ang II and inhibits AT1R-dependent vasoconstriction, revealing OA-NO ₂ as a novel antagonist of Ang II-induced hypertension.