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

Diabetologia. 2001 Apr;44(4):480-7. doi: 10.1007/s001250051646.


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-beta specific inhibitor, LY333531. Protein kinase C activities, the expression of PKC-beta II isoform and PDGF-beta 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-beta II isoform and PDGF-beta receptor protein, and proliferation activities, compared with smooth muscle cells cultured with 5.5 mmol/l glucose. Although epalrestat and LY333531 inhibited protein kinase C activation induced by glucose to the same degree, the effects of epalrestat on proliferation activities and expression of the PDGF-beta 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 LY333531 did not. The increased expression of membranous PKC-beta II 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-beta receptor, and oxidative stress, and that an aldose reductase inhibitor has a therapeutic value for this complication.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Reductase / antagonists & inhibitors
  • Animals
  • Aorta
  • Cell Division / drug effects*
  • Cells, Cultured
  • Cytosol / chemistry
  • Enzyme Inhibitors / pharmacology
  • Glucose / pharmacology*
  • Glutathione / analysis
  • Immunoblotting
  • Indoles / pharmacology
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Maleimides / pharmacology
  • Muscle, Smooth / chemistry
  • Muscle, Smooth / cytology*
  • Muscle, Smooth / drug effects
  • NAD / analysis
  • Polymers / metabolism*
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Rats
  • Receptor, Platelet-Derived Growth Factor beta / analysis
  • Rhodanine / analogs & derivatives*
  • Rhodanine / pharmacology
  • Thiazolidines


  • Enzyme Inhibitors
  • Indoles
  • Isoenzymes
  • Maleimides
  • Polymers
  • Thiazolidines
  • polyol
  • NAD
  • epalrestat
  • ruboxistaurin
  • Rhodanine
  • Aldehyde Reductase
  • Receptor, Platelet-Derived Growth Factor beta
  • Protein Kinase C
  • Glutathione
  • Glucose