Abstract
Aims/hypothesis. The protein kinase C (PKC), platelet-derived growth factor (PDGF) and polyol pathway play important parts in the hyperproliferation of 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 with or without an aldose reductase inhibitor, epalrestat, or a PKC-β specific inhibitor, LY333 531. Protein kinase C activities, the expression of PKC-βII isoform and PDGF-β receptor protein, free cytosolic NAD+:NADH ratio, the contents of reduced glutathione, and proliferation activities were measured. Results. Smooth muscle cells cultured with 20 mmol/l glucose showed statistically significant increases in protein kinase C activities, the expression of PKC-βII isoform and PDGF-β receptor protein, and proliferation activities, compared with smooth muscle cells cultured with 5.5 mmol/l glucose. Although epalrestat and LY333 531 inhibited protein kinase C activation induced by glucose to the same degree, the effects of epalrestat on proliferation activities and expression of the PDGF-β receptor were more prominent than those of LY333 531. Epalrestat improved the glucose-induced decrease in free cytosolic NAD+:NADH ratio and reduced glutathione content, but LY333 531 did not. The increased expression of membranous PKC-βII isoform was normalized by epalrestat. Conclusion/interpretation. These observations suggest that polyol pathway hyperactivity contributes to the development of diabetic macroangiopathy through protein kinase C, PDGF-β receptor, and oxidative stress, and that an aldose reductase inhibitor has a therapeutic value for this complication. [Diabetologia (2001) 44: 480–487]
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Received: 2 October 2000 and in revised form: 13 December 2000
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Nakamura, J., Kasuya, Y., Hamada, Y. et al. Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity. Diabetologia 44, 480–487 (2001). https://doi.org/10.1007/s001250051646
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DOI: https://doi.org/10.1007/s001250051646