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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:970.)
© 2005 American Heart Association, Inc.

Vascular Biology

Activator Protein-1 Mediates Shear Stress–Induced Prostaglandin D Synthase Gene Expression in Vascular Endothelial Cells

Megumi Miyagi; Yoshikazu Miwa; Fumi Takahashi-Yanaga; Sachio Morimoto; Toshiyuki Sasaguri

From the Department of Clinical Pharmacology (M.M., Y.M., F.T.-Y., S.M., T.S.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; and Third Department of Internal Medicine (M.M.), University of the Ryukyus School of Medicine, Okinawa, Japan.

Correspondence to Toshiyuki Sasaguri, MD, PhD, Department of Clinical Pharmacology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail sasaguri{at}med.kyushu-u.ac.jp

Objective— We attempted to determine the molecular mechanism of fluid shear stress–induced lipocalin-type prostaglandin D synthase (L-PGDS) expression in vascular endothelial cells.

Methods and Results— We examined the promoter region of the L-PGDS gene by loading laminar shear stress (20 dyne/cm²), using a parallel-plate flow chamber, on endothelial cells transfected with luciferase reporter vectors containing the 5'-flanking regions of the human L-PGDS gene. A deletion mutant analysis revealed that a shear stress–responsive element resided in the region between –2607 and –2523 bp. A mutation introduced into the putative binding site for activator protein-1 (AP-1) within this region eliminated the response to shear stress. In an electrophoretic mobility shift assay, shear stress stimulated nuclear protein binding to the AP-1 binding site, which was supershifted by antibodies to c-Fos and c-Jun. Shear stress elevated the c-Jun phosphorylation level in a time-dependent manner, similar to that of L-PGDS gene expression. SP600125, a c-Jun N-terminal kinase inhibitor, decreased the c-Jun phosphorylation, DNA binding of AP-1, and L-PGDS expression induced by shear stress. Additionally, an mRNA chase experiment using actinomycin D demonstrated that shear stress did not stabilize L-PGDS mRNA.

Conclusions— Shear stress induces L-PGDS expression by transcriptional activation through the AP-1 binding site.

We attempted to determine the molecular mechanism for fluid shear stress–induced lipocalin-type PG D synthase (L-PGDS) expression in endothelial cells. Examination of the promoter region of the L-PGDS gene revealed that shear stress induces L-PGDS expression by transcriptional activation through the AP-1 binding site.

Key Words: shear stress • vascular endothelial cells • PGD synthase • AP-1 • JNK

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