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

J. Nakamura, Y. Kasuya, Y. Hamada, E. Nakashima, K. Naruse, Y. Yasuda, K. Kato, N. Hotta

Research output: Contribution to journalArticle

64 Citations (Scopus)

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/1 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/1 glucose showed statistically significant increases in protein kinase C activities, the expression of PKCβII isoform and PDGF-β receptor protein, and proliferation activities, compared with smooth muscle cells cultured with 5.5 mmol/1 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 LY333531. 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.

Original languageEnglish
Pages (from-to)480-487
Number of pages8
JournalDiabetologia
Volume44
Issue number4
DOIs
Publication statusPublished - Apr 30 2001
Externally publishedYes

Keywords

  • Aldose reductase inhibitor
  • Diabetic macroangiopathy
  • Oxidative stress
  • Platelet-derived growth factor
  • Protein kinase C

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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