Abstract 8693: Knockout of p47phox Attenuates Angiotensin II-induced Endothelial Dysfunction and Vessel Damage in Vivo
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. p40phox, p47phox, p67phox and rac1. However, it is unclear about the role of p47phox (a key regulatory subunit of Nox2 activation) in mediating AngII-induced vessel dysfunction. In this study, we examined the effect of p47phox knockout (KO) on AngII-induced hypertension and aortic dissection using littermates of C57BL/6 wild-type (WT) and p47phox 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 p47phox 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 p47phox KO mice (Emax from 73.08 + 1.15% to 65.73 + 5.35%). In conclusion, p47phox plays a critical role in mediating AngII-induced endothelial dysfunction, hypertension and aortic dissection. Knockout or inhibiting p47phox may protect vessels from these AngII-induced vascular disorders.
- © 2011 by American Heart Association, Inc.