Intracellular mechanism of high d-glucose-induced modulation of vascular cell proliferation

Abstract

Development of atherosclerosis in diabetes patients is thought to be associated with high d-glucose-induccd changes in vascular cell proliferation. This study was designed to investigate the intracellular mechanisms of altered proliferation in porcine aortic endothelial and smooth muscle cells under high d-glucose conditions. Two different technical approaches were used for determination of cell proliferation, a cell counting procedure and bromodeoxyuridinc incorporation. d-Glucosc diminished endothelial cell proliferation (30.3%) and increased smooth muscle cell proliferation (143%) in a dose-dependent manner. Neither d-mannitol, sucrose nor l-glucose mimicked the effect of d-glucose. Inhibition of d-glucosc uptake into vascular cells by cytochalasin B prevented the effect of high d-glucose on cell proliferation. The aldose-reductasc inhibitors, sorbinil and zopolrestat, little affected high d-glucose-attenuated endothelial cell proliferation, while the enhanced proliferation of smooth muscle cells was prevented by aldose-reductase inhibitors. Elevation of cellular glutathione levels yielded protection of both cell types from high d-glucose-mediated changes in cell proliferation, suggesting that high d-glucose may act via generation of oxidative species. Finally, aminoguanidine was shown to constitute a very potent inhibitor of d-glucose-induced dysfunction in vascular cell proliferation. These data suggest that high d-glucose-induced changes in cell proliferation of endothelial and smooth muscle cells are related to specific d-glucose uptake rather than hyperosmolality. Aldose-reductase seems to be mainly involved in the effect of high d-glucose only on smooth muscle cell proliferation, while in endothelial cells there is (are) other factor(s) in addition to the sorbitol pathway involved in high d-glucosc-induccd changes in cell proliferation.