Endothelial NADPH oxidase 4 protects against angiotensin II-induced cardiac fibrosis and inflammation.

Aims Endothelial activation and inflammatory cell infiltration have important roles in the development of cardiac fibrosis induced by renin-angiotensin system activation. NADPH oxidases (Nox proteins) are expressed in endothelial cells (ECs) and alter their function. Previous studies indicated that Nox2 in ECs contributes to angiotensin II (AngII)-induced cardiac fibrosis. However, the effects of EC Nox4 on cardiac fibrosis are unknown. Methods and results Transgenic (TG) mice overexpressing endothelial-restricted Nox4 were studied alongside wild-type (WT) littermates as controls. At baseline, Nox4 TG mice had significantly enlarged hearts compared with WT, with elongated cardiomyocytes (increased by 18.5%, P 0.05), but there were no differences in cardiac hypertrophy or contractile function between the two groups. TG hearts displayed significantly decreased inflammatory cell infiltration with reduced levels of vascular cell adhesion molecule 1 in both the vasculature and myocardium compared with WT after AngII treatment. TG microvascular ECs stimulated with AngII in vitro supported significantly less leukocyte adhesion than WT ECs. Conclusions A chronic increase in endothelial Nox4 stimulates physiological cardiac hypertrophy and protects against AngII-induced cardiac fibrosis by inhibiting EC activation and the recruitment of inflammatory cells. Highlights Mice with endothelium-specific overexpression of Nox4 (EndoNox4 TG) exhibit eccentric hypertrophy with well-preserved cardiac function at baseline. EndoNox4 TG mice develop significantly less interstitial cardiac fibrosis in response to chronic pressure AngII stimulation, independent of cardiac hypertrophy. Overexpression of Nox4 in endothelial cells reduces AngII-induced endothelial activation. An increase in endothelial Nox4 inhibits AngII-induced recruitment of inflammatory cells in the heart.