Cholesterol-3-beta, 5-alpha, 6-beta-triol induced PI(3)K-Akt-eNOS-dependent cyclooxygenase-2 expression in endothelial cells.
Toxicol Lett
; 190(2): 172-8, 2009 Oct 28.
Article
em En
| MEDLINE
| ID: mdl-19616084
ABSTRACT
Oxidized cholesterols belong to a subgroup of oxLDLs which play major roles in atherosclerosis. In order to investigate the contribution of oxysterols from oxLDLs in atherosclerosis, cholesterol-3-beta, 5-alpha, 6-beta-triol (alpha-Triol) was studied in human umbilical vein endothelial cells. We found that alpha-Triol concentration- and time-dependently enhanced COX-2 protein expression and mRNA production followed by PGE(2) generation in human umbilical vein endothelial cells. In addition, alpha-Triol upregulated peNOS(1177) protein phosphorylation and concentration-dependently increased nitric oxide production. eNOS(1177) phosphorylation was abrogated by the PI3K inhibitor, LY294002. In studying the mechanisms involved in alpha-Triol-induced COX-2/PGE(2) production, inhibitors of NOS, PI3K, p38, and NF-kappaB, effectively attenuated COX-2 protein induction and mRNA expression, suggesting that the PI(3)K-Akt-eNOS pathway, p38MAPK, and NF-kappaB are involved in alpha-Triol-induced COX-2 expression, and following increases in p38 and Akt phosphorylation, the concentration-dependent inhibition of COX-2 protein expression by L-NAME further suggested their involvement at the translation level. We concluded that alpha-Triol increases COX-2 mRNA and protein expression via coordination with the PI(3)K-Akt-eNOS pathway and NF-kappaB. Moreover, COX-2 gene expression might be regulated by activated p38 MAPK in another unknown regulation pathway. Our findings also suggested that alpha-Triol might contribute to the effect of induced atherosclerosis in humans through COX-2 production in endothelial cells.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Colesterol
/
Fosfatidilinositol 3-Quinases
/
Células Endoteliais
/
Ciclo-Oxigenase 2
/
Óxido Nítrico Sintase Tipo III
/
Proteína Oncogênica v-akt
Limite:
Humans
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article