Intracellular mechanism of high D-glucose-induced modulation of vascular cell proliferation.
Development of atherosclerosis in diabetes patients is thought to be associated with high D-glucose-induced 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 bromodeoxyuridine incorporation. D-Glucose 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-glucose uptake into vascular cells by cytochalasin B prevented the effect of high D-glucose on cell proliferation. The aldose-reductase 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-glucose-induced changes in cell proliferation.
Graier
W F
WF
Department of Medical Biochemistry, University of Graz, Austria.
Grubenthal
I
I
Dittrich
P
P
Wascher
T C
TC
Kostner
G M
GM
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003571:Cytochalasin B / Q000494:pharmacology; D004234:Diuretics, Osmotic / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D005978:Glutathione / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D008353:Mannitol / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009994:Osmolar Concentration; D010084:Oxidation-Reduction; D013395:Sucrose / Q000494:pharmacology; D013552:Swine; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D004234:Diuretics, Osmotic; D004791:Enzyme Inhibitors; D006146:Guanidines; D003571:Cytochalasin B; D008353:Mannitol; D013395:Sucrose; D000449:Aldehyde Reductase; D014969:Xanthine Oxidase; D005978:Glutathione; D005947:Glucose; C004479:pimagedine