title: Glucose-induced hyperproliferation of cultured rat aortic smooth muscle cells through polyol pathway hyperactivity.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Third Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Nakamura
authors.forename: Y
authors.initials: Y
authors.lastname: Kasuya
authors.forename: Y
authors.initials: Y
authors.lastname: Hamada
authors.forename: E
authors.initials: E
authors.lastname: Nakashima
authors.forename: K
authors.initials: K
authors.lastname: Naruse
authors.forename: Y
authors.initials: Y
authors.lastname: Yasuda
authors.forename: K
authors.initials: K
authors.lastname: Kato
authors.forename: N
authors.initials: N
authors.lastname: Hotta
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D001011:Aorta; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D003600:Cytosol / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D005978:Glutathione / Q000032:analysis; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D009130:Muscle, Smooth / Q000737:chemistry / Q000166:cytology* / Q000187:drug effects; D009243:NAD / Q000032:analysis; D011108:Polymers / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000032:analysis; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D053778:Thiazolidines
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D011108:Polymers; D053778:Thiazolidines; C024617:polyol; D009243:NAD; C038131:epalrestat; C099154:ruboxistaurin; D012236:Rhodanine; D000449:Aldehyde Reductase; D020797:Receptor, Platelet-Derived Growth Factor beta; D011493:Protein Kinase C; D005978:Glutathione; D005947:Glucose