Oxidative stress due to the activation of a Nox2-containing NADPH oxidase is involved in Angiotensin II (AngII)-induced cardiovascular dysfunction. p47phox is a key regulatory subunit of Nox2. However, the role of p47phox in AngII-induced cardiac damage remains unclear. In this study, we used littermates of C57BL/6 wild-type (WT) and p47phox knockout (KO) mice (n=7) at the age of 10~12 months to investigate the effect of p47phox knockout on AngII-induced cardiac oxidative stress and hypertrophy. In WT mice, AngII infusion (1 mg/kg/day 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). 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. Cardiac production of reactive oxygen species (ROS) was examined by both lucigenin-chemiluminescence and DHE fluorescence. Compared to vehicle controls, AngII infusion caused two-fold increase in ROS production of WT hearts (p<0.05) (but not p47phox KO mice), which was inhibited significantly by diphenyleneiodonium (DPI, a flavoprotein inhibitor) or superoxide dismutase, significantly but slightly by NG-nitro-l-arginine methyl ester (L-NAME, a nitric oxide synthase inhibitor), but not by rotenone (mitochondrial respiratory chain inhibitor) or oxypurinol (xanthine oxidase inhibitor). Increased ROS production in WT AngII-infused hearts was accompanied by significant phosphorylation of ERK1/2. In conclusion, p47phox and p47phox signalling through ERK1/2 play an important role in AngII-induced cardiac hypertrophy.
- NADPH oxidase
- oxidative stress
- cardiac hypertrophy
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