PMID- 33418110
OWN - NLM
STAT- MEDLINE
DCOM- 20210624
LR  - 20220531
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 164
DP  - 2021 Feb 20
TI  - Endothelial Nox4 dysfunction aggravates atherosclerosis by inducing endoplasmic 
      reticulum stress and soluble epoxide hydrolase.
PG  - 44-57
LID - S0891-5849(20)32123-7 [pii]
LID - 10.1016/j.freeradbiomed.2020.12.450 [doi]
AB  - 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, IRE1alpha, 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.
CI  - Copyright (c) 2021 Elsevier Inc. All rights reserved.
FAU - Yu, Weimin
AU  - Yu W
AD  - Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, 
      Innovative Drug Research Centre, Chongqing University, Chongqing, 401331, China.
FAU - Li, Siqi
AU  - Li S
AD  - Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, 
      Innovative Drug Research Centre, Chongqing University, Chongqing, 401331, China.
FAU - Wu, Haixia
AU  - Wu H
AD  - Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, 
      Innovative Drug Research Centre, Chongqing University, Chongqing, 401331, China.
FAU - Hu, Pingping
AU  - Hu P
AD  - Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, 
      Innovative Drug Research Centre, Chongqing University, Chongqing, 401331, China. 
      Electronic address: huping07@163.com.
FAU - Chen, Lili
AU  - Chen L
AD  - Wuhan Easy Diagnosis Biomedicine Co., Ltd, Wuhan, 430075, China.
FAU - Zeng, Chunyu
AU  - Zeng C
AD  - Department of Cardiology, Daping Hospital, Third Military Medical University, 
      Chongqing, 400042, China. Electronic address: chunyuzeng01@163.com.
FAU - Tong, Xiaoyong
AU  - Tong X
AD  - Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, 
      Innovative Drug Research Centre, Chongqing University, Chongqing, 401331, China. 
      Electronic address: xiaoyongtong@cqu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210105
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - EC 1.6.3.- (NADPH Oxidase 4)
RN  - EC 1.6.3.- (Nox4 protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 3.1.- (Endoribonucleases)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
SB  - IM
MH  - Animals
MH  - *Atherosclerosis/drug therapy/genetics
MH  - *Endoplasmic Reticulum Stress
MH  - Endoribonucleases
MH  - Endothelial Cells
MH  - *Epoxide Hydrolases/genetics
MH  - Mice
MH  - *NADPH Oxidase 4/genetics
MH  - Protein Serine-Threonine Kinases
OTO - NOTNLM
OT  - Atherosclerosis
OT  - Endoplasmic reticulum stress
OT  - Endothelium
OT  - Nox4
OT  - Soluble epoxide hydrolase
EDAT- 2021/01/09 06:00
MHDA- 2021/06/25 06:00
CRDT- 2021/01/08 20:13
PHST- 2020/10/18 00:00 [received]
PHST- 2020/12/17 00:00 [revised]
PHST- 2020/12/29 00:00 [accepted]
PHST- 2021/01/09 06:00 [pubmed]
PHST- 2021/06/25 06:00 [medline]
PHST- 2021/01/08 20:13 [entrez]
AID - S0891-5849(20)32123-7 [pii]
AID - 10.1016/j.freeradbiomed.2020.12.450 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2021 Feb 20;164:44-57. doi: 
      10.1016/j.freeradbiomed.2020.12.450. Epub 2021 Jan 5.