on February 17, 2005
Published online before print February 17, 2005, doi: 10.1161/01.ATV.0000159702.68591.0d
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Submitted on August 18, 2004
Accepted on January 25, 2005
Activator Protein-1 Mediates Shear Stress-Induced Prostaglandin D Synthase Gene Expression in Vascular Endothelial Cells
Megumi Miyagi ;
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.
* To whom correspondence should be addressed. 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.
Key words: shear stress • vascular endothelial cells • PGD synthase • AP-1 • JNK
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