title: High-density lipoprotein induces cyclooxygenase-2 expression and prostaglandin I-2 release in endothelial cells through sphingosine kinase-2.
abstract: High-density lipoprotein (HDL) has a significant cardioprotective effects. HDL induces cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release in vascular endothelial cells, which contributes to its anti-atherogenic effects. However, the underlying mechanisms are not fully understood. In the present study, we observed that HDL-stimulated COX-2 expression and PGI-2 production in human umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent manner. These effects triggered by HDL were inhibited by pertussis toxin (PTX), protein kinase C (PKC) inhibitor GF109203X, and ERK inhibitor PD98059, suggesting that Gαi/Gαo-coupled GPCR, PKC, and ERK pathways are involved in HDL-induced COX-2/PGI-2 activation. More importantly, we found that silencing of sphingosine kinase 2 (SphK-2) also blocked HDL-induced COX-2/PGI-2 activation. In addition, HDL-activated SphK-2 phosphorylation accompanied by increased S1P level in the nucleus. Our ChIP data demonstrated that SphK-2 is associated with CREB at the COX-2 promoter region. Collectively, these results indicate that HDL induces COX-2 expression and PGI-2 release in endothelial cells through activation of PKC, ERK1/2, and SphK-2 pathways. These findings implicate a novel mechanism underlying anti-atherothrombotic effects of HDL.
authors.affiliation: You Country People's Hospital, Zhuzhou, 412300, Hunan, China, xslyxry@163.com.
authors.forename: Sheng-Lin
authors.initials: SL
authors.lastname: Xiong
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Yi
mesh_terms: D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D051546:Cyclooxygenase 2; D011464:Epoprostenol; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D008075:Lipoproteins, HDL; D048052:Mitogen-Activated Protein Kinase 3; D017853:Phosphotransferases (Alcohol Group Acceptor); D011493:Protein Kinase C; D043562:Receptors, G-Protein-Coupled; D000099157:Sphingosine Kinase; C496540:PTGS2 protein, human