Endothelial Nox4-based NADPH oxidase regulates atherosclerosis via soluble epoxide hydrolase

Pingping Hu, Xiaojuan Wu, Alok R. Khandelwal, Weimin Yu, Zaicheng Xu, Lili Chen, Jian Yang, Robert M. Weisbrod, Kin Sing Stephen Lee, Francesca Seta, Bruce D. Hammock, Richard A. Cohen, Chunyu Zeng, Xiaoyong Tong

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Nox4-based NADPH oxidase is a major reactive oxygen species-generating enzyme in the vasculature, but its role in atherosclerosis remains controversial. Objective Our goal was to investigate the mechanisms of endothelial Nox4 in regulating atherosclerosis. Approach and results Atherosclerosis-prone conditions (disturbed blood flow, type I diabetes, and Western diet) downregulated endothelial Nox4 mRNA in arteries. To address whether the downregulated endothelial Nox4 was directly involved in the development of atherosclerosis, we generated mice carrying a human Nox4 P437H dominant negative mutation (Nox4DN), driven by the endothelial specific promoter Tie-2, on atherosclerosis-prone genetic background (ApoE deficient mice) to mimic the effect of decreased endothelial Nox4. Nox4DN significantly increased type I diabetes-induced aortic stiffness and atherosclerotic lesions. Gene analysis indicated that soluble epoxide hydrolase 2 (sEH) was significantly upregulated in Nox4DN endothelial cells (EC). Inhibition of sEH activity in Nox4DN EC suppressed inflammation and macrophage adhesion to EC. On the contrary, overexpression of endothelial wild type Nox4 suppressed sEH, ameliorated Western diet-induced atherosclerosis and decreased aortic stiffness. Conclusions Atherosclerosis-prone conditions downregulated endothelial Nox4 to accelerate the progress of atherosclerosis, at least in part, by upregulating sEH to enhance inflammation.

Original languageEnglish (US)
Pages (from-to)1382-1391
Number of pages10
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1863
Issue number6
DOIs
StatePublished - Jun 1 2017

Keywords

  • Atherosclerosis
  • Endothelium
  • Nox4
  • Soluble epoxide hydrolase 2
  • Type I diabetes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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    Hu, P., Wu, X., Khandelwal, A. R., Yu, W., Xu, Z., Chen, L., Yang, J., Weisbrod, R. M., Lee, K. S. S., Seta, F., Hammock, B. D., Cohen, R. A., Zeng, C., & Tong, X. (2017). Endothelial Nox4-based NADPH oxidase regulates atherosclerosis via soluble epoxide hydrolase. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1863(6), 1382-1391. https://doi.org/10.1016/j.bbadis.2017.02.004