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Cardiovascular Research 2005 67(1):134-141; doi:10.1016/j.cardiores.2005.02.022
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Copyright © 2005, European Society of Cardiology

Troglitazone and 15-deoxy-{Delta}12,14-prostaglandin J2 inhibit shear-induced coupling factor 6 release in endothelial cells

Hirofumi Tomitaa, Tomohiro Osanaia, Tsutomu Tokib, Satoko Sasakia, Naotaka Maedaa, Reiichi Murakamia, Koji Magotad, Minoru Yasujimac and Ken Okumuraa,*

aThe Second Department of Internal Medicine, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562 Japan
bDepartment of Pediatrics, Hirosaki University School of Medicine, Hirosaki, 036-8562 Japan
cDepartment of Laboratory Medicine, Hirosaki University School of Medicine, Hirosaki, 036-8562 Japan
dDaiichi Suntory Biomedical Research Co., Ltd., Osaka, 618-8503 Japan

* Corresponding author. Tel.: +81 172 39 5057; fax: +81 172 35 9190. Email address: okumura{at}cc.hirosaki-u.ac.jp

Objective: We previously showed that mitochondrial coupling factor 6 (CF6), an endogenous inhibitor of prostacyclin synthesis and a vasoconstrictor, is present on the surface of human umbilical vein endothelial cells (HUVEC) and is released outside of the cells by shear stress. We investigated the intracellular signaling mechanism for shear-induced release of CF6 in HUVEC and the effects of troglitazone and 15-deoxy-{Delta}12,14-prostaglandin J2 (15d-PGJ2), both peroxisome proliferator-activated receptor (PPAR)-{gamma} ligands, on it.

Methods and results: The release and gene expression of CF6 in HUVEC were enhanced by shear stress at 25 dyn/cm2, measured by radioimmunoassay and real-time RT-PCR, respectively. The intracellular content of CF6 was decreased after exposure to shear stress at 25 dyn/cm2. Transfection experiments with deletional and mutational CF6 promoter constructs, and with dominant negative mutant I{kappa}B kinase {alpha} (K44M) demonstrated that shear-induced CF6 transcription was dependent on nuclear factor-kappa B (NF-{kappa}B) activation. Pretreatment with troglitazone or 15d-PGJ2 inhibited the shear-induced release and gene expression of CF6, whereas fenofibric acid, a PPAR-{alpha} ligand, had no influence on them. Western blot and immunostaining showed that troglitazone and 15d-PGJ2 inhibited the shear-induced, reactive oxygen species (ROS)-mediated activation of NF-{kappa}B at the level of I{kappa}B protein.

Conclusions: The shear-induced gene expression and release of CF6 in HUVEC are mediated by the ROS-related activation of NF-{kappa}B signaling pathway. Troglitazone and 15d-PGJ2 inhibit them at the I{kappa}B protein level.

KEYWORDS Coupling factor 6; Shear stress; Vascular endothelial cells; PPAR-{gamma} ligands; Nuclear factor-kappa B

Time for primary review 27 days


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