Endothelial Nox4 dysfunction aggravates atherosclerosis by inducing endoplasmic reticulum stress and soluble epoxide hydrolase
Autor: | Weimin Yu, Chunyu Zeng, Xiaoyong Tong, Siqi Li, Haixia Wu, Lili Chen, Pingping Hu |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Epoxide hydrolase 2 medicine.medical_specialty Endothelium Inflammation Protein Serine-Threonine Kinases Biochemistry Proinflammatory cytokine Mice 03 medical and health sciences 0302 clinical medicine Physiology (medical) Internal medicine Endoribonucleases medicine Animals Epoxide Hydrolases NADPH oxidase biology ATF6 Chemistry Endothelial Cells NOX4 Atherosclerosis Endoplasmic Reticulum Stress 030104 developmental biology medicine.anatomical_structure Endocrinology NADPH Oxidase 4 cardiovascular system biology.protein Unfolded protein response medicine.symptom 030217 neurology & neurosurgery |
Zdroj: | Free Radical Biology and Medicine. 164:44-57 |
ISSN: | 0891-5849 |
Popis: | 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. |
Databáze: | OpenAIRE |
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