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J. Biol. Chem., Vol. 283, Issue 9, 5699-5707, February 29, 2008

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Cell Type-specific Post-transcriptional Regulation of Production of the Potent Antiangiogenic and Proatherogenic Protein Thrombospondin-1 by High Glucose^*

Sanghamitra Bhattacharyya¹, Tina E. Marinic¹, Irene Krukovets, George Hoppe, and Olga I. Stenina²

From the Department of Molecular Cardiology and Joseph J. Jacobs Center for Thrombosis and Vascular Biology and the Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio 44026

Hyperglycemia is an independent risk factor for development of vascular diabetic complications. Vascular dysfunction in diabetics manifests in a tissue-specific manner; macrovasculature is affected by atherosclerotic lesions, and microvascular complications are described as "aberrant angiogenesis": in the same patient angiogenesis is increased in some tissues (e.g. retinal neovascularization) and decreased in others (e.g. in skin). Molecular cell- and tissue-specific mechanisms regulating the response of vasculature to hyperglycemia remain unclear. Thrombospondin-1 (TSP-1), a potent antiangiogenic and proatherogenic protein, has been implicated in the development of several vascular diabetic complications (atherosclerosis, nephropathy, and cardiomyopathy). This study examines cell type-specific regulation of production of thrombospondin-1 by high glucose. We previously reported the increased expression of TSP-1 in the large arteries of diabetic animals. mRNA and protein levels were up-regulated in response to high glucose. Unlike in macrovascular cells, TSP-1 protein levels are dramatically decreased in response to high glucose in microvascular endothelial cells and retinal pigment epithelial cells (RPE). This down-regulation is post-transcriptional; mRNA levels are increased. In situ mRNA hybridization and immunohistochemistry revealed that the level of mRNA is up-regulated in RPE of diabetic rats, whereas the protein level is decreased. This cell type-specific posttranscriptional suppression of TSP-1 production in response to high glucose in microvascular endothelial cells and RPE is controlled by untranslated regions of TSP-1 mRNA that regulate coupling of TSP-1 mRNA to polysomes and its translation. The cell-specific regulation of TSP-1 suggests a potential mechanism for the aberrant angiogenesis in diabetics and TSP-1 involvement in development of various vascular diabetic complications.

Received for publication, August 3, 2007 , and in revised form, December 18, 2007.

^* This work was supported by National Institutes of Health Grants K01 DK62128, P50 HL077107, and R01 DK067532, American Heart Association Grant 0565284B, funds from the Lerner Research Institute (Cleveland Clinic Foundation) (to O. I. S.), and by American Heart Association Grant 0555235B (to G. H.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed. NB50, 9500 Euclid Ave., Cleveland, OH 44195. Fax: 216-445-8204; E-mail: stenino{at}ccf.org.

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