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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1319.)
© 2007 American Heart Association, Inc.

Vascular Biology

Acrolein Induces Cyclooxygenase-2 and Prostaglandin Production in Human Umbilical Vein Endothelial Cells

Roles of p38 MAP Kinase

Yong Seek Park; Jayoung Kim; Yoshiko Misonou; Rina Takamiya; Motoko Takahashi; Michael R. Freeman; Naoyuki Taniguchi

From the Department of Biochemistry (Y.S.P., Y.M., R.T., M.T., N.T.) and the Department of Disease Glycomics, Research Institute for Microbial Diseases (N.T.), Osaka University, Japan; the Department of Microbiology (Y.S.P.), College of Medicine, Kyung Hee University, Seoul, Korea; and the Urological Diseases Research Center (J.K., M.R.F.), Children’s Hospital Boston, Harvard Medical School, Boston, Mass.

Correspondence to Naoyuki Taniguchi, MD, PhD, Department of Disease Glycomics, Research Institute for Microbial Diseases, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail tani52{at}wd5.so-net.ne.jp

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.

Methods and Results— Cyclooxygenase (COX)-2 induction by acrolein and signal pathways were measured using Western blots, Northern blots, immunoflouresence, 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 C (PKC), abrogated the upregulation of COX-2 at both protein and mRNA levels.

Conclusion— 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 PKC and p38 MAPK are required for transcriptional activation of COX-2.

The present study demonstrates that acrolein, a known toxin in tobacco smoke, stimulates expression of COX-2 and enhances PG synthesis in endothelial cells through activation of PKC, p38 MAPK, and CREB pathway. Our finding suggests that acrolein may play a role in progression of atherosclerosis.

Key Words: acrolein • COX-2 • p38 MAPK • atherosclerosis • endothelial cells