Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity

Aims/hypothesis. The protein kinase C (PKC), platelet-derived growth factor (PDGF) and polyol pathway play important parts in the hyperproliferation o f smooth muscle cells, a characteristic feature of diabetic macroangiopathy . The precise mechanism, however, remains unclear. This study investigated the relation between polyol pathway, protein kinase C and platelet-derived growth factor in the development of diabetic macroangiopathy. Methods. Smooth muscle cells were cultured with 5.5 or 20 mmol/l glucose wi th or without an aldose reductase inhibitor, epalrestat, or a PKC-beta spec ific inhibitor, LY333 531. Protein kinase C activities, the expression of P KC-beta II isoform and PDGF-beta receptor protein, free cytosolic NAD(+):NA DH ratio, the contents of reduced glutathione, and proliferation activities were measured. Results. Smooth muscle cells cultured with 20 mmol/l glucose showed statist ically significant increases in protein kinase C activities, the expression of PKC-beta II isoform and PDGF-beta receptor protein, and proliferation a ctivities, compared with smooth muscle cells cultured with 5.5 mmol/l gluco se. Although epalrestat and LY333 531 inhibited protein kinase C activation induced by glucose to the same degree, the effects of epalrestat on prolif eration activities and expression of the PDGF-beta receptor were more promi nent than those of LY333 531. Epalrestat improved the glucose-induced decre ase in free cytosolic NAD(+):NADH ratio and reduced glutathione content, bu t LY333 531 did not. The increased expression of membranous PKC-beta II iso form was normalized by epalrestat. Conclusion/interpretation. These observations suggest that polyol pathway h yperactivity contributes to the development of diabetic macroangiopathy thr ough protein kinase C, PDGF-beta receptor, and oxidative stress, and that a n aldose reductase inhibitor has a therapeutic value for this complication.