Cell type-specific post-transcriptional regulation of production of the potent antiangiogenic and proatherogenic protein thrombospondin-1 by high glucose.
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.
Bhattacharyya
Sanghamitra
S
Department of Molecular Cardiology and Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Cleveland Clinic, Cleveland, Ohio 44026, USA.
Marinic
Tina E
TE
Krukovets
Irene
I
Hoppe
George
G
Stenina
Olga I
OI
D020533:Angiogenesis Inhibitors / Q000096:biosynthesis*; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D002478:Cells, Cultured; D048909:Diabetes Complications / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D017403:In Situ Hybridization; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000378:metabolism*; D009928:Organ Specificity / Q000187:drug effects; D010857:Pigment Epithelium of Eye / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D013549:Sweetening Agents / Q000494:pharmacology*; D019700:Thrombospondin 1 / Q000096:biosynthesis*
D020533:Angiogenesis Inhibitors; D013549:Sweetening Agents; D019700:Thrombospondin 1; D005947:Glucose