Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

J. Biol. Chem. 282 (8): 5704-5714

© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Glycosylation Mediates Up-regulation of a Potent Antiangiogenic and Proatherogenic Protein, Thrombospondin-1, by Glucose in Vascular Smooth Muscle Cells*

Priya Raman{ddagger}, Irene Krukovets{ddagger}, Tina E. Marinic{ddagger}, Paul Bornstein§, , and Olga I. Stenina{ddagger}1

{ddagger}Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic, Cleveland, Ohio 44195 and §Departments of Biochemistry and Medicine, School of Medicine, University of Washington, Seattle, Washington 98195

Abstract: Accelerated development of atherosclerotic lesions remains the most frequent and dangerous complication of diabetes, accounting for 80% of deaths among diabetics. However, our understanding of the pathways mediating glucose-induced gene expression in vascular cells remains controversial and incomplete. We have identified an intracellular metabolic pathway activated by high glucose in human aortic smooth muscle cells that mediates up-regulation of thrombospondin-1 (TSP-1). TSP-1 is a potent antiangiogenic and proatherogenic protein that may represent an important link between diabetes and vascular complications. Using different glucose analogs and metabolites sharing distinct, limited metabolic steps with glucose, we demonstrated that activation of TSP-1 transcription is mediated by the hexosamine pathway of glucose catabolism, possibly resulting in modulation of the activity of nuclear proteins activity through their glycosylation. Specific inhibitors of glutamine: fructose 6-phosphate amidotransferase (GFAT), an enzyme controlling the hexosamine pathway, as well as direct inhibitors of protein glycosylation efficiently inhibited TSP-1 transcription and the activity of a TSP-1 promoter-reporter construct stimulated by high glucose. Overexpression of recombinant GFAT resulted in increased TSP-1 levels. Pharmacological inhibition of GFAT or protein glycosylation inhibited increased proliferation of human aortic smooth muscle cells caused by glucose. We have demonstrated that the hexosamine metabolic pathway mediates up-regulation of TSP-1 by high glucose. Our results suggest that the hexosamine pathway and intracellular glycosylation may control important steps in initiation and development of atherosclerotic lesions.


Received for publication November 28, 2006. Revision received December 18, 2006.

* This work was supported by National Institutes of Health Grants R01 DK067532, K01 DK62128, and P50 HL077107, American Heart Association Grant 0565284B, and funds from the Lerner Research Institute (Cleveland Clinic) (to O. I. S.) and by National Institutes of Health Grant R01 45418 (to P. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom correspondence should be addressed: Dept. of Molecular Cardiology, Cleveland Clinic, 9500 Euclid Ave., NB50, Cleveland, OH 44195. Tel.: 216-444-9057; Fax: 216-445-8204; E-mail: stenino{at}ccf.org.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Thrombospondin-1 Induction in the Diabetic Myocardium Stabilizes the Cardiac Matrix in Addition to Promoting Vascular Rarefaction Through Angiopoietin-2 Upregulation.
C. Gonzalez-Quesada, M. Cavalera, A. Biernacka, P. Kong, D.-W. Lee, A. Saxena, O. Frunza, M. Dobaczewski, A. Shinde, and N. G. Frangogiannis (2013)
Circ. Res. 113, 1331-1344
   Abstract »    Full Text »    PDF »
Novel Tissue-Specific Mechanism of Regulation of Angiogenesis and Cancer Growth in Response to Hyperglycemia.
S. Bhattacharyya, K. Sul, I. Krukovets, C. Nestor, J. Li, and O. S. Adognravi (2012)
JAHA 1, e005967
   Abstract »    Full Text »    PDF »
Feeding Sugar to Tumors: With a Supplement of miR?.
O. P. Blanc-Brude and A. Tedgui (2012)
JAHA 1, e006213
   Full Text »    PDF »
Role of UDP-N-Acetylglucosamine (GlcNAc) and O-GlcNAcylation of Hyaluronan Synthase 2 in the Control of Chondroitin Sulfate and Hyaluronan Synthesis.
D. Vigetti, S. Deleonibus, P. Moretto, E. Karousou, M. Viola, B. Bartolini, V. C. Hascall, M. Tammi, G. De Luca, and A. Passi (2012)
J. Biol. Chem. 287, 35544-35555
   Abstract »    Full Text »    PDF »
Upregulation of thrombospondin-1 expression by leptin in vascular smooth muscle cells via JAK2- and MAPK-dependent pathways.
R. J. Chavez, R. M. Haney, R. H. Cuadra, R. Ganguly, R. K. Adapala, C. K. Thodeti, and P. Raman (2012)
Am J Physiol Cell Physiol 303, C179-C191
   Abstract »    Full Text »    PDF »
Differential Gene Expression Profile in Bovine Blastocysts Resulting from Hyperglycemia Exposure During Early Cleavage Stages.
G. L. M. Cagnone, I. Dufort, C. Vigneault, and M.-A. Sirard (2012)
Biol Reprod 86, 50
   Abstract »    Full Text »    PDF »
The Thrombospondins.
J. C. Adams and J. Lawler (2011)
Cold Spring Harb Perspect Biol 3, a009712
   Abstract »    Full Text »    PDF »
A Novel Transcriptional Mechanism of Cell Type-Specific Regulation of Vascular Gene Expression by Glucose.
P. Raman, C. Harry, M. Weber, I. Krukovets, and O. I. Stenina (2011)
Arterioscler Thromb Vasc Biol 31, 634-642
   Abstract »    Full Text »    PDF »
Glucose downregulation of PKG-I protein mediates increased thrombospondin1-dependent TGF-{beta} activity in vascular smooth muscle cells.
S. Wang, T. M. Lincoln, and J. E. Murphy-Ullrich (2010)
Am J Physiol Cell Physiol 298, C1188-C1197
   Abstract »    Full Text »    PDF »
Hexosamine biosynthesis pathway flux promotes endoplasmic reticulum stress, lipid accumulation, and inflammatory gene expression in hepatic cells.
A. T Sage, L. A Walter, Y. Shi, M. I. Khan, H. Kaneto, A. Capretta, and G. H. Werstuck (2010)
Am J Physiol Endocrinol Metab 298, E499-E511
   Abstract »    Full Text »    PDF »
Regulation of Plasma Fructose and Mortality in Mice by the Aldose Reductase Inhibitor Lidorestat.
H.-L. Noh, Y. Hu, T.-S. Park, T. DiCioccio, A. J. Nichols, K. Okajima, S. Homma, and I. J. Goldberg (2009)
J. Pharmacol. Exp. Ther. 328, 496-503
   Abstract »    Full Text »    PDF »
Protein O-GlcNAcylation: a new signaling paradigm for the cardiovascular system.
B. Laczy, B. G. Hill, K. Wang, A. J. Paterson, C. R. White, D. Xing, Y.-F. Chen, V. Darley-Usmar, S. Oparil, and J. C. Chatham (2009)
Am J Physiol Heart Circ Physiol 296, H13-H28
   Abstract »    Full Text »    PDF »
Integrin-Associated Protein Association With Src Homology 2 Domain Containing Tyrosine Phosphatase Substrate 1 Regulates IGF-I Signaling In Vivo.
L. A. Maile, B. E. Capps, E. C. Miller, A. W. Aday, and D. R. Clemmons (2008)
Diabetes 57, 2637-2643
   Abstract »    Full Text »    PDF »
Aryl Hydrocarbon Receptor Is Activated by Glucose and Regulates the Thrombospondin-1 Gene Promoter in Endothelial Cells.
P. Dabir, T. E. Marinic, I. Krukovets, and O. I. Stenina (2008)
Circ. Res. 102, 1558-1565
   Abstract »    Full Text »    PDF »
Protein Modification by O-Linked GlcNAc Reduces Angiogenesis by Inhibiting Akt Activity in Endothelial Cells.
B. Luo, Y. Soesanto, and D. A. McClain (2008)
Arterioscler Thromb Vasc Biol 28, 651-657
   Abstract »    Full Text »    PDF »
Cell Type-specific Post-transcriptional Regulation of Production of the Potent Antiangiogenic and Proatherogenic Protein Thrombospondin-1 by High Glucose.
S. Bhattacharyya, T. E. Marinic, I. Krukovets, G. Hoppe, and O. I. Stenina (2008)
J. Biol. Chem. 283, 5699-5707
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882