THE EFFECTS OF GLUCOSE-INDUCED OXIDATIVE STRESS ON GROWTH AND EXTRACELLULAR-MATRIX GENE-EXPRESSION OF VASCULAR SMOOTH-MUSCLE CELLS

Vascular smooth muscle cell (VSMC) dysfunction plays a role in diabeti c macrovasculopathy and this map include abnormalities in growth chara cteristics and the extracellular matrix. As the actual mechanisms by w hich glucose induces VSMC dysfunction remain unclear, the aim of this study was to assess the potential role of glucose-induced oxidative st ress. Porcine aortic VSMCs were cultured for 10 days in either 5 mmol/ l normal glucose or 25 mmol/l D-glucose (high glucose). There was evid ence of oxidative stress as indicated by a 50 % increase in intracellu lar malondialdehyde (p < 0.05), increased mRNA expression of CuZn supe roxide dismutase and Mn superoxide dismutase (by 51 % and 37 % respect ively, p < 0.01) and a 50 % decrease in glutathione in 25 mmol/l D-glu cose (p < 0.001). Growth was increased by 25.0 % (p < 0.01), mRNA expr ession of extracellular matrix proteins (collagens I, III. IV and fibr onectin) was not altered by high glucose in these experimental conditi ons. Repletion of glutathione with N-acetyl L-cysteine (1 mmol/l) in V SMC grown in high glucose was associated with reduction in malondialde hyde and restored growth to that of normal glucose. The water soluble analogue of vitamin E, Trolox (200 mu mol/l), reduced malondialdehyde concentrations, but had no effect on glutathione depletion or the incr eased growth rate seen with high glucose. The addition of buthionine s ulphoximine (10 mu mol/l) to VSMC cultured in normal glucose reduced g lutathione, increased malondialdehyde and increased growth to a simila r extent as that found in high glucose alone. These results suggest th at thiol status, rather than lipid peroxides, is a key factor in modul ating VSMC growth and that mRNA expression of extracellular matrix pro teins is not increased in VSMC under conditions of glucose-induced oxi dative stress.