Nitro-oleic acid inhibits angiotensin II-induced hypertension.
BACKGROUND
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.


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)gamma 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.
Zhang
Jifeng
J
Cardiovascular Center, College of Engineering, University of Michigan, USA.
Villacorta
Luis
L
Chang
Lin
L
Fan
Zhenzhen
Z
Hamblin
Milton
M
Zhu
Tianqing
T
Chen
Chen S
CS
Cole
Marsha P
MP
Schopfer
Francisco J
FJ
Deng
Cheri X
CX
Garcia-Barrio
Minerva T
MT
Feng
Ying-Hong
YH
Freeman
Bruce A
BA
Chen
Y Eugene
YE
D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000502:physiology / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control*; D008041:Linoleic Acids / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009574:Nitro Compounds / Q000627:therapeutic use*; D019301:Oleic Acid / Q000627:therapeutic use*; D009829:Oleic Acids / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley
C501855:10-nitro-9,12-octadecadienoic acid; C521487:10-nitro-oleic acid; D008041:Linoleic Acids; D009574:Nitro Compounds; D009829:Oleic Acids; D000804:Angiotensin II; D019301:Oleic Acid