Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase

Angiotensin (ANG) II (AngII) and aldosterone contribute to the development of interstitial cardiac fibrosis. We investigated the potential role of a Nox2-containing NADPH oxidase in aldosterone-induced fibrosis and the involvement of this mechanism in AngII-induced effects. Nox2(-/-) mice were compared with matched wild-type controls (WT). In WT mice, subcutaneous (s.c.) AngII (1.1 mg/kg/day for 2 wk) significantly increased NADPH oxidase activity, interstitial fibrosis (11.5 +/- 1.0% vs. 7.2 +/- 0.7%; P <0.05), expression of fibronectin, procollagen I, and connective tissue growth factor mRNA, MMP-2 activity, and NF-kB activation. These effects were all inhibited in Nox(-/-) hearts. The mineralocorticoid receptor antagonist spironolactone inhibited AngII-induced increases in NADPH oxidase activity and the increase in interstitial fibrosis. In a model of mineralocorticoiddependent hypertension involving chronic aldosterone infusion (0.2 mg/kg/day) and a 1% Na Cl diet ("ALDO"), WT animals exhibited increased NADPH oxidase activity, pro-fibrotic gene expression, MMP-2 activity, NF-kB activation, and significant interstitial cardiac fibrosis (12.0 +/- 1.7% with ALDO vs. 6.3 +/- 0.3% without; P <0.05). These effects were inhibited in Nox2(-/-) ALDO mice (e.g., fibrosis 6.8 +/- 0.8% with ALDO vs. 5.8 +/- 1.0% without ALDO; P=NS). These results suggest that aldosterone-dependent activation of a Nox2-containing NADPH oxidase contributes to the profibrotic effect of AngII in the heart as well as the fibrosis seen in mineralocorticoid-dependent hypertension