High glucose enhances inducible nitric oxide synthase expression. Role of protein kinase C-betaII.
The aim was to determine whether high glucose levels interfere with nitric oxide (NO) production and inducible NO synthase (iNOS) protein expression in interleukin-1beta-stimulated vascular smooth muscle cells from normotensive Wistar Kyoto and spontaneously hypertensive rats. Cells were incubated with either normal (5.5 mM) or high (22 mM) d-glucose for 72 h and with interleukin-1beta (10 ng/ml) for the last 24 h. High glucose increased nitrite levels, iNOS expression and protein kinase C activity in cells from normotensive rats and had no effect in cells from hypertensive rats. High glucose effects on nitrite production and iNOS expression was abolished by the selective inhibitor for the protein kinase C-betaII, 5,21:12,17-dimetheno-18H-dibenzo[i,o]pyrrolo[3,4-1] [1,8]diacyclohexadecine-18,20 (19H)-dione, 8-[(dimethylamino) methyl]-6,7,8,9,10,11-hexahydro-monomethanesulfonate (LY379196, 30 nM). Calphostin C (1 microM) and LY379196 (10 microM) reduced nitrite levels and iNOS expression only in cells from normotensive rats treated with both media. These results suggest that high glucose increases inducible nitric oxide synthase induction and subsequent NO production by activating the protein kinase C-betaII; this mechanism seems to be altered in hypertension.
Pacheco
María E
ME
Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/ Arzobispo Morcillo 4, 28029 Madrid, Spain.
Beltrán
Amada
A
Redondo
Juliana
J
Manso
Ana M
AM
Alonso
María J
MJ
Salaices
Mercedes
M
D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D015153:Blotting, Western; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D008698:Mesylates / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D064546:Protein Kinase C beta; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013755:Tetradecanoylphorbol Acetate / 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; D007375:Interleukin-1; D008698:Mesylates; D009281:Naphthalenes; D011758:Pyrroles; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D011493:Protein Kinase C; D064546:Protein Kinase C beta; C058819:calphostin C; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate