Published online before print October 6, 2005, doi: 10.1161/01.RES.0000189260.46084.e5
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Submitted on August 15, 2005
Revised on September 8, 2005
Accepted on September 22, 2005
Calreticulin Destabilizes Glucose Transporter-1 mRNA in Vascular Endothelial and Smooth Muscle Cells Under High-Glucose Conditions
Hana Toraty-Jain ;
From the Department of Pharmacology (H.T.-J., Y.R., S.S.), School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel; The Nephrology (T.N.-M.) and Endocrinology & Metabolism (N.K.) Services, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and Department of Clinical Biochemistry and Pathobiochemistry (J.E.), German Diabetes Center, Düsseldorf, Germany.
* To whom correspondence should be addressed. E-mail: sassolo{at}cc.huji.ac.il.
Substrate autoregulation of glucose transporter-1 (GLUT-1) mRNA and protein expression provides vascular endothelial and smooth muscle cells a sensitive mechanism to adapt their rate of glucose transport in response to changing glycemic conditions. Hyperglycemia-induced downregulation of glucose transport is particularly important in protecting these cells against an excessive influx of glucose and consequently increased intracellular protein glycation and generation of free radicals; both are detrimental in the development of vascular disease in diabetes. We aimed to investigate the molecular mechanism of high glucose-induced downregulation of GLUT-1 mRNA expression in primary bovine aortic vascular endothelial (VEC) and vascular smooth muscle (VSMC) cell cultures. Using RNA mobility shift, UV cross-linking, and in vitro degradation assays, followed by mass-spectrometric analysis, we identified calreticulin as a specific destabilizing trans-acting factor that binds to a 10-nucleotide cis-acting element (CAE2181 to 2190) in the 3'-untranslated region of GLUT-1 mRNA. Pure calreticulin accelerated the rate of GLUT-1 mRNA-probe degradation in vitro, whereas overexpression of calreticulin in vascular cells decreased significantly the total cell content of GLUT-1 mRNA and protein. The expression of calreticulin was augmented in vascular cells exposed to high glucose in comparison with low-glucose conditions. Similarly, increased expression of calreticulin was observed in aortae of diabetic Psammomys obesus in comparison with normoglycemic controls. These data suggest that CAE2181 to 2190-calreticulin complex, which is formed in VSMC and VEC exposed to hyperglycemic conditions, renders GLUT-1 mRNA susceptible to degradation. This interaction underlies the process of downregulation of glucose transport in vascular cells under high-glucose conditions.
Key words: calreticulin • glucose transporter-1 • hyperglycemia • mRNA turnover • vascular smooth muscle cells • vascular endothelial cells
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