Endothelial Nox4 dysfunction aggravates atherosclerosis by inducing endoplasmic reticulum stress and soluble epoxide hydrolase.

Abstract

BACKGROUND AND AIMS:

Our previous findings have demonstrated the protective effect of endothelial Nox4-based NADPH oxidase on atherosclerosis. One of the possible mechanisms is the inhibition of soluble epoxide hydrolase (sEH), a proinflammatory and atherogenic factor. Our goal was to investigate whether in vivo inhibition of sEH by 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) alleviates endothelial Nox4 dysfunction caused atherosclerosis and the regulatory mechanism of endothelial Nox4 on sEH.

METHODS:

& results: We used endothelial human Nox4 dominant-negative (EDN) transgenic mice in ApoE deficient background to mimic the dysfunction of endothelial Nox4 in atherosclerosis-prone conditions. In EDN aortic endothelium, sEH and the inflammatory marker vascular cell adhesion molecule 1 (VCAM1) were upregulated. TPPU reduced atherosclerotic lesions in EDN mice. In EDN endothelial cells (ECs), the endoplasmic reticulum (ER) stress markers (BIP, IRE1α, phosphorylation of PERK, ATF6) were upregulated, and they can be suppressed by ER stress inhibitor 4-phenyl butyric acid (4-PBA). In EDN ECs, 4-PBA downregulated the expression of sEH and VCAM1, suppressed inflammation, and its application in vivo reduced atherosclerotic lesions of EDN mice.

CONCLUSIONS:

Endothelial Nox4 dysfunction upregulated sEH to enhance inflammation, probably by its induction of ER stress. Inhibition of ER stress or sEH is beneficial to alleviate atherosclerosis caused by endothelial Nox4 dysfunction.

• Authors: Weimin Yu, Siqi Li, Haixia Wu, Pingping Hu, Lili Chen, Chunyu Zeng, Xiaoyong Tong
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 164 Pg. 44-57 (02 20 2021) ISSN: 1873-4596 [Electronic] United States
• PMID: 33418110 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• NADPH Oxidase 4
• Nox4 protein, mouse
• Protein Serine-Threonine Kinases
• Endoribonucleases
• Epoxide Hydrolases

Topics

• Animals
• Atherosclerosis (drug therapy, genetics)
• Endoplasmic Reticulum Stress
• Endoribonucleases
• Endothelial Cells
• Epoxide Hydrolases (genetics)
• Mice
• NADPH Oxidase 4 (genetics)
• Protein Serine-Threonine Kinases