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KMID : 1007320140200010021
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Journal of the Korean Society of Menopause
2014 Volume.20 No. 1 p.21 ~ p.31
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Mitochondrial Channel Opener Diazoxide Attenuates Hyp-oxia-Induced sFlt-1 Release in Human Choriocarcinoma Cells
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Shin Byeong-Seop
Kim Hwi-Gon
Choi Ook-Hwan
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Abstract
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Objective: To examine the effect of diazoxide on hypoxia-induced soluble fms-like tyrosin kinase-1 (sFlt-1) release in JEG-3 choriocarcinoma cells.
Methods: Cells were cultured under normoxia (20% O2) or hypoxia (1% O2), and expression of sFlt-1 mRNA and protein release was determined by quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) assays and enzyme-linked immunosorbent assay (ELISA).
Results: Tumor necrosis factor-alpha (TNF-α) as well as hypoxia stimulated sFlt-1 release and diazoxide inhibited both of them. The selective inhibitor of mitochondrial adenosine triphosphat (ATP)-sensitive K+ channel opener (KATP) 5-hydroxydecanoate (5-HD) completely reversed the diazoxide-induced inhibition of hypoxia-stimulated sFlt-1 release. qRT-PCR and Western blot analyses showed that diazoxide up-regulated the heme oxygenase-1 (HO-1) expression. In addition, the HO-1 inducer cobalt protoporphyrin (CoPP) and the metabolic product of HO-1 bilirubin mimicked diazoxide to inhibit sFlt-1 release and reactive oxygen species (ROS) production under hypoxia, whereas the HO-1 inhibitor zinc protoporphyrin IX (ZnPP IX) antagonized the effect of diazoxide. In cells transfected with the HO-1 siRNA, diazoxide did not exert any effect on sFlt-1 release and ROS production under hypoxia.
Conclusion: These results, taken together, strongly suggest that up-regulation of the HO-1 expression is the crucial mechanism responsible for the diazoxide-induced inhibition of the sFlt-1 release and ROS production under hypoxia.
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KEYWORD
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Diazoxide, Heme oxygenase-1, Reactive oxygen speciese, Vascular endothelial growth factor receptor-1
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