High glucose abolishes the antiproliferative effect of 17beta-estradiol in human vascular smooth muscle cells.
We examined effects of 17beta-estradiol (E(2)) on human vascular smooth muscle cell (VSMC) proliferation under normal (5 mmol/l) and high (25 mmol/l) glucose concentrations. Platelet-derived growth factor (PDGF) BB (20 ng/ml)-induced increases in DNA synthesis and proliferation were greater in high than normal glucose concentrations; the difference in DNA synthesis was abolished by a protein kinase C (PKC)-beta inhibitor, LY-379196 (30 nmol/l). Western blotting showed that PKC-beta(1) protein increased in cells exposed to high glucose, whereas PKC-alpha protein and total PKC activity remained unchanged, compared with normal glucose cultures. In normal glucose, E(2) (1-100 nmol/l) inhibited PDGF-induced DNA synthesis by 18-37% and cell proliferation by 16-22% in a concentration-dependent manner. The effects of E(2) were blocked by the estrogen receptor (ER) antagonist ICI-182780, indicating ER dependence. In high glucose, the inhibitory effect of E(2) on VSMC proliferation was abolished but was restored in the presence of the PKC-beta inhibitor LY-379196. Thus high glucose enhances human VSMC proliferation and attenuates the antiproliferative effect of E(2) in VSMC via activation of PKC-beta.
Ling
Shanhong
S
Hormones and the Vasculature Laboratory, Baker Medical Research Institute, Melbourne, Victoria 8008, Australia.
Little
Peter J
PJ
Williams
Maro R I
MR
Dai
Aozhi
A
Hashimura
Kazuhiko
K
Liu
Jun-Ping
JP
Komesaroff
Paul A
PA
Sudhir
Krishnankutty
K
D000077214:Becaplermin; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D005947:Glucose / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D008698:Mesylates / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011758:Pyrroles / Q000494:pharmacology
C434605:5,21 - 12,17-dimetheneo-18H-dibenzo(i,o)pyrrolo(3,4-1)(1,8)diazacyclohexandecine-18,10(19H)dione,8((dimethylamino)methyl)-6,7,8,9,10,11-hexahydro,monomethanesulfonate; D004791:Enzyme Inhibitors; D004965:Estrogen Antagonists; D008698:Mesylates; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011758:Pyrroles; D000077214:Becaplermin; D000077267:Fulvestrant; D004958:Estradiol; D004247:DNA; D011493:Protein Kinase C; D005947:Glucose