Format

Send to:

Choose Destination
See comment in PubMed Commons below
J Biol Chem. 2014 Oct 31;289(44):30625-34. doi: 10.1074/jbc.M114.571984. Epub 2014 Sep 4.

Unspliced X-box-binding protein 1 (XBP1) protects endothelial cells from oxidative stress through interaction with histone deacetylase 3.

Author information

  • 1From the Cardiovascular Division, King's College London, London SE5 9NU, United Kingdom.
  • 2the Department of Emergency Medicine, the Second Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an 710004, China.
  • 3the Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Institute of Clinical Sciences, Belfast BT12 6BL, United Kingdom.
  • 4the Centre Laboratory, 305th Hospital of the People's Liberation Army, Beijing 100017, China, and.
  • 5the Sino-German Laboratory for Molecular Medicine, Key Laboratory for Clinical Cardiovascular Genetics, Ministry of Education, FuWai Hospital, Chinese Academy of Medical Sciences, Beijing 100037, China.
  • 6From the Cardiovascular Division, King's College London, London SE5 9NU, United Kingdom, qingbo.xu@kcl.ac.uk.
  • 7From the Cardiovascular Division, King's College London, London SE5 9NU, United Kingdom, lingfang.zeng@kcl.ac.uk.

Abstract

It is well known that atherosclerosis occurs geographically at branch points where disturbed flow predisposes to the development of plaque via triggering of oxidative stress and inflammatory reactions. In this study, we found that disturbed flow activated anti-oxidative reactions via up-regulating heme oxygenase 1 (HO-1) in an X-box-binding protein 1 (XBP1) and histone deacetylase 3 (HDAC3)-dependent manner. Disturbed flow concomitantly up-regulated the unspliced XBP1 (XBP1u) and HDAC3 in a VEGF receptor and PI3K/Akt-dependent manner. The presence of XBP1 was essential for the up-regulation of HDAC3 protein. Overexpression of XBP1u and/or HDAC3 activated Akt1 phosphorylation, Nrf2 protein stabilization and nuclear translocation, and HO-1 expression. Knockdown of XBP1u decreased the basal level and disturbed flow-induced Akt1 phosphorylation, Nrf2 stabilization, and HO-1 expression. Knockdown of HDAC3 ablated XBP1u-mediated effects. The mammalian target of rapamycin complex 2 (mTORC2) inhibitor, AZD2014, ablated XBP1u or HDAC3 or disturbed flow-mediated Akt1 phosphorylation, Nrf2 nuclear translocation, and HO-1 expression. Neither actinomycin D nor cycloheximide affected disturbed flow-induced up-regulation of Nrf2 protein. Knockdown of Nrf2 abolished XBP1u or HDAC3 or disturbed flow-induced HO-1 up-regulation. Co-immunoprecipitation assays demonstrated that XBP1u physically bound to HDAC3 and Akt1. The region of amino acids 201 to 323 of the HDAC3 protein was responsible for the binding to XBP1u. Double immunofluorescence staining revealed that the interactions between Akt1 and mTORC2, Akt1 and HDAC3, Akt1 and XBP1u, HDAC3, and XBP1u occurred in the cytosol. Thus, we demonstrate that XBP1u and HDAC3 exert a protective effect on disturbed flow-induced oxidative stress via up-regulation of mTORC2-dependent Akt1 phosphorylation and Nrf2-mediated HO-1 expression.

© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

KEYWORDS:

Cell Signaling; Endothelial Cell; Histone Deacetylase (HDAC); Oxidative Stress; Shear Stress

PMID:
25190803
[PubMed - indexed for MEDLINE]
PMCID:
PMC4215241
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk