© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Tumor necrosis factor 
as an endogenous stimulator for circulating coupling factor 6
aThe Second Department of Internal Medicine, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan
bDaiichi Suntory Biomedical Research CO., LTD., Osaka 618-8513, Japan
* Corresponding author. Tel.: +81-172-39-5057; fax: +81-172-35-9190. Email address: osanait{at}cc.hirosaki-u.ac.jp
Objective: We recently showed that mitochondrial coupling factor 6 (CF6) is present as a pressor substance and a prostacyclin inhibitor in systemic circulation. However, the regulation mechanism for circulating CF6 is unknown. We investigated the role of tumor necrosis factor-
(TNF-) in the generation and release of CF6. Methods and results: We used two kinds of cells, human umbilical vein endothelial cells (HUVEC) and ECV-304. The concentration of CF6 in the medium increased with time in both ECV-304 and HUVEC. Treatment of ECV-304 and HUVEC with TNF- enhanced the release of CF6 in a dose-dependent manner concomitantly with the decrease in CF6 content in the mitochondria at 24 h. The released CF6 was characterized to be an active full-length peptide by Western blot. The ratio of CF6 to GAPDH mRNA, measured by real-time polymerase chain reaction, was 1.7 fold increased at 1 h after exposure to TNF- in ECV-304 and HUVEC. This enhanced gene expression and release was blocked or suppressed by 70% by stable transfection of dominant negative mutant I
B kinase whose efficacy was confirmed by blockade of translocation of NF-B p65 protein and of degradation of IB protein. Flow cytometry analysis revealed that the cell surface-associated CF6 was significantly increased at 24 h after TNF- in a dose-dependent manner. Conclusions: TNF- stimulates the gene expression of CF6 via activation of NF-B signaling pathway, and promotes the release of CF6 from ECV-304 and HUVEC.
KEYWORDS Prostacyclin; Coupling factor 6; Tumor necrosis factor ; Vascular endothelial cells; Nuclear factor B
Time for primary review 16 days
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