Aldose reductase inhibitor improves insulin-mediated glucose uptake and prevents migration of human coronary artery smooth muscle cells induced by high glucose

Abstract —We examined involvement of the polyol pathway in high glucose–induced human coronary artery smooth muscle cell (SMC) migration using Boyden’s chamber method. Chronic glucose treatment for 72 hours potentiated, in a concentration-dependent manner (5.6 to 22.2 mol/L), platelet-derived growth factor (PDGF) BB–mediated SMC migration. This potentiation was accompanied by an increase in PDGF BB binding, because of an increased number of PDGF-β receptors, and this potentiation was blocked by the aldose reductase inhibitor epalrestat. Epalrestat at concentrations of 10 and 100 nmol/L inhibited high glucose–potentiated (22.2 mmol/L), PDGF BB–mediated migration. Epalrestat at 100 nmol/L inhibited a high glucose–induced increase in the reduced/oxidized nicotinamide adenine dinucleotide ratio and membrane-bound protein kinase C (PKC) activity in SMCs. PKC inhibitors calphostin C (100 nmol/L) and chelerythrine (1 μmol/L) each inhibited high glucose–induced, PDGF BB–mediated SMC migration. High glucose–induced suppression of insulin-mediated [ 3 H]-deoxyglucose uptake, which was blocked by both calphostin C (100 nmol/L) and chelerythrine (1 μmol/L), was decreased by epalrestat (100 nmol/L). Chronic high glucose treatment for 72 hours increased intracellular oxidative stress, which was directly measured by flow cytometry using carboxydichlorofluorescein diacetate bis-acetoxymethyl ester, and this increase was significantly suppressed by epalrestat (100 nmol/L). Antisense oligonucleotide to PKC-β isoform inhibited high glucose–mediated changes in SMC migration, insulin-mediated [ 3 H]-deoxyglucose uptake, and oxidative stress. These findings suggest that high glucose concentrations potentiate SMC migration in coronary artery and that the aldose reductase inhibitor epalrestat inhibits high glucose–potentiated, PDGF BB–induced SMC migration, possibly through suppression of PKC (PKC-β), impaired insulin-mediated glucose uptake, and oxidative stress.