The Journal of Experimental Medicine
Avanti Polar Lipids, Inc.
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
A correction to this article has been published: El-Osta et al., J. Exp. Med. 205 (11) 2683
Published online
doi:10.1084/jem.20081188
The Journal of Experimental Medicine, Vol. 205, No. 10, 2409-2417
The Rockefeller University Press, 0022-1007 $30.00
© El-Osta et al.
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 2286K)
Right arrow PPT slides of all figures
Right arrow Supplemental Material Index
Right arrow Related biobytes podcast
Right arrow Correction (v205,p2683)
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by El-Osta, A.
Right arrow Articles by Brownlee, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by El-Osta, A.
Right arrow Articles by Brownlee, M.
Right arrowPubmed/NCBI databases
*Gene*GEO Profiles
*HomoloGene*UniGene
*Compound via MeSH
*Substance via MeSH
Medline Plus Health Information
*Diabetes
Hazardous Substances DB
*GLUCOSE
Related Collections
Right arrowRelated In this Issue article
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

ARTICLE

 Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia

Assam El-Osta1, Daniella Brasacchio1, Dachun Yao3, Alessandro Pocai4, Peter L. Jones5, Robert G. Roeder6, Mark E. Cooper2,3, and Michael Brownlee3

1 Diabetes and Metabolism Division, Baker Epigenetics in Human Health and Disease, and 2 Diabetes and Metabolism Division, Juvenile Diabetes Research Foundation Danielle Alberti Memorial Centre for Diabetic Complications, Baker IDI Heart and Diabetes Institute, the Alfred Medical Research and Education Precinct, Commercial Road, Melbourne, Victoria 3004, Australia
3 Juvenile Diabetes Research Foundation International Center for Diabetic Complications Research and 4 Department of Medicine and Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461
5 Department of Cell and Structural Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61802
6 Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, NY 10021

CORRESPONDENCE Assam El-Osta: assam.el-osta{at}bakeridi.edu.au OR Michael Brownlee: brownlee{at}aecom.yu.edu

The current goal of diabetes therapy is to reduce time-averaged mean levels of glycemia, measured as HbA1c, to prevent diabetic complications. However, HbA1c only explains <25% of the variation in risk of developing complications. Because HbA1c does not correlate with glycemic variability when adjusted for mean blood glucose, we hypothesized that transient spikes of hyperglycemia may be an HbA1c–independent risk factor for diabetic complications. We show that transient hyperglycemia induces long-lasting activating epigenetic changes in the promoter of the nuclear factor {kappa}B (NF-{kappa}B) subunit p65 in aortic endothelial cells both in vitro and in nondiabetic mice, which cause increased p65 gene expression. Both the epigenetic changes and the gene expression changes persist for at least 6 d of subsequent normal glycemia, as do NF-{kappa}B–induced increases in monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1 expression. Hyperglycemia-induced epigenetic changes and increased p65 expression are prevented by reducing mitochondrial superoxide production or superoxide-induced {alpha}-oxoaldehydes. These results highlight the dramatic and long-lasting effects that short-term hyperglycemic spikes can have on vascular cells and suggest that transient spikes of hyperglycemia may be an HbA1c–independent risk factor for diabetic complications.

Abbreviations used: BAEC, bovine aortic endothelial cell; ChIP, chromatin immunoprecipitation; cChIP, carrier ChIP; CVD, cardiovascular disease; GLO1, glyoxalase 1; H3k4me1, histone 3 lysine 4 monomethylation; H3K4me2, H3K4 dimethylation; H3K4me3, H3K4 trimethylation 4; HAEC, human aortic endothelial cell; HG, high glucose; HMT, histone methyltransferases; LCM, laser capture microdissection; LG, low glucose; MCP-1 monocyte chemoattractant protein 1; MnSOD, manganese superoxide dismutase; ROS, reactive oxygen species; TSA, trichostatin A; TSS, transcription start site; UCP-1, uncoupling protein 1; VCAM-1, vascular cell adhesion molecule 1.

D. Brasacchio and D. Yao contributed equally to this paper.

© 2008 El-Osta et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?

Related In this Issue article

The lowdown on sugar highs
Hema Bashyam
J. Exp. Med. 2008 205: 2183. [Full Text] [PDF]



This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS