PMID- 30292945
OWN - NLM
STAT- MEDLINE
DCOM- 20190401
LR  - 20190401
IS  - 2213-2317 (Electronic)
IS  - 2213-2317 (Linking)
VI  - 20
DP  - 2019 Jan
TI  - Homocysteine causes vascular endothelial dysfunction by disrupting endoplasmic 
      reticulum redox homeostasis.
PG  - 46-59
LID - S2213-2317(18)30658-X [pii]
LID - 10.1016/j.redox.2018.09.021 [doi]
AB  - Endothelial dysfunction induced by hyperhomocysteinemia (HHcy) plays a critical 
      role in vascular pathology. However, little is known about the role of 
      endoplasmic reticulum (ER) redox homeostasis in HHcy-induced endothelial 
      dysfunction. Here, we show that Hcy induces ER oxidoreductin-1alpha (Ero1alpha) 
      expression with ER stress and inflammation in human umbilical vein endothelial 
      cells and in the arteries of HHcy mice. Hcy upregulates Ero1alpha expression by 
      promoting binding of hypoxia-inducible factor 1alpha to the ERO1A promoter. Notably, 
      Hcy rather than other thiol agents markedly increases the GSH/GSSG ratio in the 
      ER, therefore allosterically activating Ero1alpha to produce H(2)O(2) and trigger ER 
      oxidative stress. By contrast, the antioxidant pathway mediated by ER glutathione 
      peroxidase 7 (GPx7) is downregulated in HHcy mice. Ero1alpha knockdown and GPx7 
      overexpression protect the endothelium from HHcy-induced ER oxidative stress and 
      inflammation. Our work suggests that targeting ER redox homeostasis could be used 
      as an intervention for HHcy-related vascular diseases.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Wu, Xun
AU  - Wu X
AD  - National Laboratory of Biomacromolecules, CAS Center for Excellence in 
      Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 
      100101, China; College of Life Sciences, University of Chinese Academy of 
      Sciences, Beijing 100049, China.
FAU - Zhang, Lihui
AU  - Zhang L
AD  - National Laboratory of Biomacromolecules, CAS Center for Excellence in 
      Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 
      100101, China; College of Life Sciences, University of Chinese Academy of 
      Sciences, Beijing 100049, China.
FAU - Miao, Yutong
AU  - Miao Y
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Key Laboratory of Molecular 
      Cardiovascular Science, Ministry of Education, Beijing 100191, China.
FAU - Yang, Juan
AU  - Yang J
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Key Laboratory of Molecular 
      Cardiovascular Science, Ministry of Education, Beijing 100191, China.
FAU - Wang, Xian
AU  - Wang X
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Key Laboratory of Molecular 
      Cardiovascular Science, Ministry of Education, Beijing 100191, China.
FAU - Wang, Chih-Chen
AU  - Wang CC
AD  - National Laboratory of Biomacromolecules, CAS Center for Excellence in 
      Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 
      100101, China; College of Life Sciences, University of Chinese Academy of 
      Sciences, Beijing 100049, China.
FAU - Feng, Juan
AU  - Feng J
AD  - Department of Physiology and Pathophysiology, School of Basic Medical Sciences, 
      Peking University Health Science Center, Key Laboratory of Molecular 
      Cardiovascular Science, Ministry of Education, Beijing 100191, China. Electronic 
      address: juanfeng@bjmu.edu.cn.
FAU - Wang, Lei
AU  - Wang L
AD  - National Laboratory of Biomacromolecules, CAS Center for Excellence in 
      Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 
      100101, China; College of Life Sciences, University of Chinese Academy of 
      Sciences, Beijing 100049, China. Electronic address: wanglei@moon.ibp.ac.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180926
PL  - Netherlands
TA  - Redox Biol
JT  - Redox biology
JID - 101605639
RN  - 0 (Reactive Oxygen Species)
RN  - 0LVT1QZ0BA (Homocysteine)
SB  - IM
MH  - Animals
MH  - Endoplasmic Reticulum/*metabolism
MH  - Endothelial Cells/*metabolism
MH  - Endothelium, Vascular/*metabolism
MH  - *Homeostasis
MH  - Homocysteine/*metabolism
MH  - Humans
MH  - *Oxidation-Reduction
MH  - Reactive Oxygen Species/metabolism
PMC - PMC6174864
OTO - NOTNLM
OT  - Endoplasmic reticulum
OT  - Endothelial cells
OT  - Ero1alpha
OT  - GPx7
OT  - Homocysteine
OT  - Redox homeostasis
EDAT- 2018/10/08 06:00
MHDA- 2019/04/02 06:00
PMCR- 2018/09/26
CRDT- 2018/10/08 06:00
PHST- 2018/07/27 00:00 [received]
PHST- 2018/09/18 00:00 [revised]
PHST- 2018/09/26 00:00 [accepted]
PHST- 2018/10/08 06:00 [pubmed]
PHST- 2019/04/02 06:00 [medline]
PHST- 2018/10/08 06:00 [entrez]
PHST- 2018/09/26 00:00 [pmc-release]
AID - S2213-2317(18)30658-X [pii]
AID - 10.1016/j.redox.2018.09.021 [doi]
PST - ppublish
SO  - Redox Biol. 2019 Jan;20:46-59. doi: 10.1016/j.redox.2018.09.021. Epub 2018 Sep 
      26.