Sphingosine 1‑phosphate induced by hypoxia increases the expression of PAI‑1 in HepG2 cells via HIF‑1α.
|
| Abstract |
Our group has recently reported that in the immortal human HepG2 liver cell line, sphingosine 1‑phosphate (S1P) increases transcription of plasminogen activator inhibitor type‑1 (PAI‑1), the major physiological inhibitor of fibrinolysis, within 4 h. The present study aimed to elucidate the molecular mechanisms underlying this effect. PAI‑1 expression was measured by reverse transcription‑quantitative polymerase chain reaction and immunoblotting. It was demonstrated that S1P increased PAI‑1 promoter activity but did not increase the activity of promoters lacking the hypoxia responsive element (HRE) 2. In addition, S1P transiently increased the concentration of hypoxia inducible factor (HIF)‑1α, a transcription factor capable of binding to HRE. When HIF‑1α was knocked down, the induction of transcription of PAI‑1 by S1P was no longer observed. Sphingosine kinase (SPHK) activity is increased by hypoxia. It was demonstrated that increases in the concentration of the HIF‑1α protein induced by hypoxia were prevented by treatment with SPHK inhibitor or S1P receptor antagonists. Thus, modification of the induction of HIF‑1α by S1P, leading to increased transcription of PAI‑1, may be an attractive therapeutic target for thrombosis and consequent inhibition of fibrinolysis associated with hypoxia.
|
|---|---|
| Authors | Akimasa Sanagawa, Soichiro Iwaki, Moyoko Asai, Daisuke Sakakibara, Hiroaki Norimoto, Burton E Sobel, Satoshi Fujii |
| Journal | Molecular medicine reports (Mol Med Rep) Vol. 14 Issue 2 Pg. 1841-8 (Aug 2016) ISSN: 1791-3004 [Electronic] Greece |
| PMID | 27357063 (Publication Type: Journal Article) |
| Chemical References |
|
| Topics |
|
Join CureHunter, for free Research Interface BASIC access!
Realize the full power of the drug-disease research graph!