Abstract 13713: The H2O2-Producing NADPH Oxidase Nox4 Protects Against Angiotensin II-Induced Vascular Hypertrophy and Inflammation
Nox4 is a NADPH oxidase ubiquitously expressed in vascular cells. Different to all other Noxes, Nox4 constitutively produces H2O2. We hypothesize that this basal H2O2 formation desensitizes against the redox-mediated signaling of cytokines and growth factors. We generated systemic as well as tamoxifen-inducible Nox4−/− mice. In systemic Nox4−/− mice, Nox4 protein expression was absent in the lung, the kidney and in cultured lung endothelial cells. Tamoxifen-treatment of inducible Nox4−/− mice also induced a robust reduction of Nox4. Amplex red assay revealed reduced basal H2O2 in cultured lung endothelial cells from Nox4−/− mice and a loss of the TGFβ1-induced H2O2 formation. Organ bath experiments demonstrated that basal endothelial function of aortic rings of WT and Nox4−/− was identical but that TGFβ1 induced an attenuation of relaxation only in wild type (WT) mice. Interestingly, H2O2 selectively attenuated responses in Nox4−/− rings pretreated with TGFβ1 so that in the presence of H2O2 and TGFβ1 responses between rings from Nox4−/− and WT mice were identical. In vivo treatment with angiotensin II (AII) revealed no difference between WT and Nox4−/− mice with respect to hypertension development. However, when we acutely deleted Nox4 by tamoxifen an attenuation of vascular function in response to AII was observed: Compared to WT animals, aortae from acutely Nox4-deficient animals had higher mass and medial hypertrophy in response to AII and developed significantly greater endothelial dysfunction. Importantly, as judged by qRT-PCR, a significantly greater degree of inflammation was present in acutely Nox4-deficient mice in response to AII as documented by a greater expression of IL-1β, IL-6, TNF-α and TGFβ1 and the macrophage marker EMR−1. We conclude that the constitutive H2O2 formation by Nox4 adjusts the vascular redox-balance and protects vessels from vascular remodeling and inflammation induced by AII.
- © 2010 by American Heart Association, Inc.