Metformin prevents glucose-induced protein kinase C-β2 activation in human umbilical vein endothelial cells through an antioxidant mechanism

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Abstract

Hyperglycemia determines the vascular complications of diabetes through different mechanisms: one of these is excessive activation of the isoform β2 of protein kinase C (PKC-β2). 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-β2 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-β2 activation by developing adenovirally expressed chimeras encoding fusion protein between green fluorescent protein (GFP) and conventional β2 isoform (PKC-β2-GFP). Glucose (25 mmol/l) induced the translocation of PKC-β2-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-β2-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-β2 translocation because of a direct antioxidant effect. Our data substantiate the findings of previous large intervention studies on the beneficial effect of this drag in type 2 diabetic patients. © 2005 by the American Diabetes Association.

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Gallo, A., Ceolotto, G., Pinton, P., Iori, E., Murphy, E., Rutter, G. A., … Avogaro, A. (2005). Metformin prevents glucose-induced protein kinase C-β2 activation in human umbilical vein endothelial cells through an antioxidant mechanism. Diabetes, 54(4), 1123–1131. https://doi.org/10.2337/diabetes.54.4.1123

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