Methylglyoxal mediates vascular inflammation via JNK and p38 in human endothelial cells.
Methylglyoxal (MGO) is a reactive metabolite of glucose. Since the plasma concentration of MGO is increased in diabetic patients, MGO is implicated in diabetes-associated vascular endothelial cells (ECs) injury, which might be responsible for atherosclerosis. In the present study, we examined effects of treatment of human umbilical vein ECs with MGO on EC morphology and inflammatory responses. MGO (24 h) induced cytotoxic morphological changes in a concentration-dependent manner (0-420 microM). MGO induced mRNA and protein expression of cyclooxygenase (COX)-2 in a concentration (0-420 microM)- and time (6-24 h)-dependent manner. COX-2 induction was associated with increased PGE(2) release. Acute treatment with MGO (20 min) induced concentration-dependent (0-420 microM) activation of JNK and p38 MAP kinase but not ERK or NF-kappaB. Both the JNK inhibitor SP600125 and the p38 inhibitor SB203580 prevented the MGO induction of COX-2. However, inhibiting JNK and p38 or COX-2 was ineffective to the morphological damage by MGO (420 microM, 24 h). EUK134, a synthetic combined superoxide dismutase/catalase mimetic, had no effect on MGO-induced COX-2. Present results indicated that MGO mediates JNK- and p38-dependent EC inflammatory responses, which might be independent of oxidative stress. On the other hand, MGO-induced morphological cell damage seems unlikely to be associated with COX-2-PGE(2).
Dept. of Veterinary Pharmacology, Kitasato University., Towada, Aomori 034-8628, Japan. yamawaki@vmas.kitasato-u.ac.jp
Hideyuki
H
Yamawaki
Kazuaki
K
Saito
Muneyoshi
M
Okada
Yukio
Y
Hara
D015153:Blotting, Western; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D011765:Pyruvaldehyde / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014471:Umbilical Veins / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*
D012333:RNA, Messenger; D011765:Pyruvaldehyde; D051546:Cyclooxygenase 2; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone