Acrolein induces cyclooxygenase-2 and prostaglandin production in human umbilical vein endothelial cells: roles of p38 MAP kinase.
OBJECTIVE
Acrolein, a known toxin in tobacco smoke, might be involved in atherogenesis. This study examined the effect of acrolein on expression of cyclooxygenase-2 (COX-2) and prostaglandin (PG) production in endothelial cells.


RESULTS
Cyclooxygenase (COX)-2 induction by acrolein and signal pathways were measured using Western blots, Northern blots, immunofluorescence, ELISA, gene silencing, and promoter assay. Colocalization of COX2 and acrolein-adduct was determined by immunohistochemistry. Here we report that the levels of COX-2 mRNA and protein are increased in human umbilical vein endothelial cells (HUVECs) after acrolein exposure. COX-2 was found to colocalize with acrolein-lysine adducts in human atherosclerotic lesions. Inhibition of p38 MAPK activity abolished the induction of COX-2 protein and PGE2 accumulation by acrolein, while suppression of extracellular signal-regulated kinase (ERK) and JNK activity had no effect on the induction of COX-2 expression in experiments using inhibitors and siRNA. Furthermore, rottlerin, an inhibitor of protein kinase Cdelta (PKCdelta), abrogated the upregulation of COX-2 at both protein and mRNA levels.


CONCLUSIONS
These results provide that acrolein may play a role in progression of atherosclerosis and new information on the signaling pathways involved in COX-2 upregulation in response to acrolein and provide evidence that PKCdelta and p38 MAPK are required for transcriptional activation of COX-2.
Park
Yong Seek
YS
Department of Biochemistry, Research Institute for Microbial Diseases, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Kim
Jayoung
J
Misonou
Yoshiko
Y
Takamiya
Rina
R
Takahashi
Motoko
M
Freeman
Michael R
MR
Taniguchi
Naoyuki
N
D000098:Acetophenones / Q000494:pharmacology; D000171:Acrolein / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000378:metabolism*; D001578:Benzopyrans / Q000494:pharmacology; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D012907:Smoking / Q000009:adverse effects; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000098:Acetophenones; D001578:Benzopyrans; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D007093:Imidazoles; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D000171:Acrolein; C085746:rottlerin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C093642:SB 203580