Abstract 8693: Knockout of p47 phox Attenuates Angiotensin II-induced Endothelial Dysfunction and Vessel Damage in Vivo

Abstract

Increased bioavailability and activity of angiotensin II (AngII) have been found to be associated with vascular oxidative stress derived from a Nox2 enzyme. The Nox2 has several regulatory subunits i.e. p40 phox , p47 phox , p67 phox and rac1. However, it is unclear about the role of p47 phox (a key regulatory subunit of Nox2 activation) in mediating AngII-induced vessel dysfunction. In this study, we examined the effect of p47 phox knockout (KO) on AngII-induced hypertension and aortic dissection using littermates of C57BL/6 wild-type (WT) and p47 phox KO mice (n=7) at the age of 10~12 months. In WT mice, AngII infusion (1.15mg/kg/day delivered by osmotic mini-pump for 14 days) increased significantly the systolic blood pressure (SBP) from 127 + 13 to 172 + 11 mmHg, and this was accompanied with significant indication of cardiac hypertrophy (heart/body weight ratio increased ~17.9 + 0.1%) as compared to vehicle infused controls (P < 0.05), and 3 out of 7 AngII-infused WT mice developed aortic dissection. However, in p47 phox KO mice, AngII infusion caused a mild increase in SBP (from 119 + 9 to 149 + 10 mmHg, P<0.05) without significant increase in heart/body weight ratio, and there was no aortic dissection in AngII-infused KO mice. Aorta organ bath showed that AngII-infusion reduced significantly the endothelium-dependent vessel relaxation to acetylcholine in WT mice (Emax from 82.10 + 8.73% to 54.37 + 6.91%, P < 0.05), which can be returned to the control level by adding a superoxide scavenger, tiron. However, AngII had no significant effect on endothelium-dependent vessel relaxation to acetylcholine in the p47 phox KO mice (Emax from 73.08 + 1.15% to 65.73 + 5.35%). In conclusion, p47 phox plays a critical role in mediating AngII-induced endothelial dysfunction, hypertension and aortic dissection. Knockout or inhibiting p47 phox may protect vessels from these AngII-induced vascular disorders.