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Metformin Prevents Glucose-Induced Protein Kinase C-ß2 Activation in Human Umbilical Vein Endothelial Cells Through an Antioxidant Mechanism

¹ Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy
² Department of Experimental and Diagnostic Medicine Section of General Pathology, University of Ferrara, Ferrara, Italy
³ Henry Wellcome Laboratories for Integrated Cell Signalling, Department of Biochemistry, University of Bristol, Bristol, U.K

Hyperglycemia determines the vascular complications of diabetes through different mechanisms: one of these is excessive activation of the isoform ß2 of protein kinase C (PKC-ß2). Metformin, a widely used antidiabetic agent, is associated with decreased cardiovascular mortality in obese type 2 diabetic patients. Therefore, we assessed the role of metformin in glucose-induced activation of PKC-ß2 and determined the mechanism of its effect in human umbilical venous endothelial cells grown to either normo- (5 mmol/l) or hyperglycemia (10 mmol/l) and moderately and acutely exposed to 25 mmol/l glucose. We studied PKC-ß2 activation by developing adenovirally expressed chimeras encoding fusion protein between green fluorescent protein (GFP) and conventional ß2 isoform (PKC-ß2–GFP). Glucose (25 mmol/l) induced the translocation of PKC-ß2–GFP from the cytosol to the membrane in cells grown to hyperglycemia but not in those grown in normal glucose medium. Metformin (20 µmol/l) prevented hyperglycemia-induced PKC-ß2–GFP translocation. We also assessed oxidative stress under the same conditions with a 4-((9-acridine-carbonyl)amino)-2,2,6,6-tetramethylpiperidin-oxyl,free radical (TEMPO-9-AC) fluorescent probe. We observed significantly increased radical oxygen species production in cells grown in hyperglycemia medium, and this effect was abolished by metformin. We show that in endothelial cells, metformin inhibits hyperglycemia-induced PKC-ß2 translocation because of a direct antioxidant effect. Our data substantiate the findings of previous large intervention studies on the beneficial effect of this drug in type 2 diabetic patients.

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