Nitro-Oleic Acid Inhibits Angiotensin II–Induced Hypertension

Abstract

Rationale: Nitro-oleic acid (OA-NO 2 ) is a bioactive, nitric-oxide derived fatty acid with physiologically relevant vasculoprotective properties in vivo. OA-NO 2 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-NO 2 in angiotensin (Ang) II–induced hypertension. Methods and Results: We show that systemic administration of OA-NO 2 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-NO 2 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 (AT 1 R)-mediated signaling because vascular contraction by other G-protein–coupled receptors is not altered in response to OA-NO 2 treatment. From the mechanistic viewpoint, OA-NO 2 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 AT 1 R, reduces heterotrimeric G-protein coupling, and inhibits IP 3 (inositol-1,4,5-trisphosphate) and calcium mobilization, without inhibiting Ang II binding to the receptor. Conclusions: These results demonstrate that OA-NO 2 diminishes the pressor response to Ang II and inhibits AT 1 R-dependent vasoconstriction, revealing OA-NO 2 as a novel antagonist of Ang II–induced hypertension.