Key result
Nox4 deletion accelerates atherosclerosis and impairs endothelial function in Ldlr knockout mice.
Why the study?
The role of Nox4-derived H2O2 in protecting against endothelial dysfunction and atherosclerosis development in LDL receptor deficient mice was unclear.
Does genetic deletion of Nox4 worsen endothelial dysfunction and atherosclerosis in Ldlr knockout mice?
Does genetic deletion of Nox4 worsen endothelial dysfunction and atherosclerosis in Ldlr knockout mice?
Nox4 plays a protective role against endothelial dysfunction and atherosclerosis, suggesting that Nox4-derived H2O2 is vasoprotective.
Answers are grounded in this paper and cite their sources.
No implications for current clinical practice; leaves open Nox4 as a therapeutic target in atherosclerosis.
AIMS: Endothelial dysfunction is an early step in the development of atherosclerosis. Increased formation of superoxide anions by NADPH oxidase Nox1, 2, and 5 reduces nitric oxide availability and can promote endothelial dysfunction. In contrast, recent evidence supports a vasoprotective role of H2O2 produced by main endothelial isoform Nox4. Therefore, we analysed the impact of genetic deletion of Nox4 on 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 due to high-fat diet increased atherosclerotic plaque burden and galectin-3 staining in Nox4(-/-)/Ldlr(-/-) mice compared with Ldlr(-/-) mice. Under physiological conditions, loss of Nox4 does not influence aortic vascular function. In this setting, loss of Nox4-derived H2O2 production could be partially compensated for by nNOS upregulation. Using an innovative optical coherence tomography approach, we were able to analyse endothelial function by flow-mediated vasodilation in the murine saphenous artery in vivo. This new approach revealed an altered flow-mediated dilation in Nox4(-/-) mice, indicating a role for Nox4 under physiological conditions in peripheral arteries in vivo. CONCLUSIONS: Nox4 plays an important role in maintaining endothelial function under physiological and pathological conditions. Loss of Nox4-derived H2O2 could be partially compensated for by nNOS upregulation, but severe endothelial dysfunction is not reversible. This leads to increased atherosclerosis under atherosclerotic prone conditions.
No takes yet. Share an insight, caveat, or question.
Langbein et al. (2015) studied Endothelial dysfunction and atherosclerosis. Genetic deletion of Nox4 vs. Ldlr(-/-) mice (without Nox4 deletion) was evaluated on Endothelial function and atherosclerotic plaque burden. Genetic deletion of Nox4 in Ldlr knockout mice impaired endothelial function and increased atherosclerotic plaque burden compared with Ldlr(-/-) mice.
Synapse has enriched 10 related papers. Consider them for comparative context: