Abstract
Introduction: Endothelial dysfunction is an early step in the development of atherosclerosis. Increased formation of superoxide anions by NADPH oxidase Nox1, 2 and 5 reduce NO availability and can promote endothelial dysfunction. In contrast, recent evidence supports a vasoprotective role of H2O2 produced by main endothelial isoform Nox4. Therefore, we assessed the hypothesis genetic deletion of Nox4 influences endothelial dysfunction and atherosclerosis in the low-density lipoprotein receptor (Ldlr) knockout model. Methods and Results: Ex vivo analysis of endothelial function by Mulvany myograph showed impaired endothelial function in thoracic aorta of Nox4-/-/Ldlr-/- mice. Further progression of endothelial dysfunction by high-fat diet increased atherosclerotic plaque burden and galectin-3 staining in Nox4-/-/Ldlr-/- mice compared to Ldlr-/- mice. In addition, we obtained evidence that under physiological conditions the loss of Nox4-derived H2O2 production could partially be compensated by nNOS upregulation. Using a self-developed optical coherence tomography device we were able to analyse endothelial function by flow-mediated vasodilation in the murine saphenous artery in vivo. This new approach observed an altered flow-mediated dilation in Nox4-/- mice, indicating a role for Nox4 under physiological conditions in vivo likewise. Conclusion: Nox4 plays an important role under physiological and pathological conditions to maintain endothelial function. Loss of Nox4-derived H2O2 could partially be compensated by nNOS upregulation, but severe endothelial dysfunction is not reversible. This leads to increased atherosclerosis under atherosclerotic prone conditions.
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