title: Human apolipoprotein A-I induces cyclooxygenase-2 expression and prostaglandin I-2 release in endothelial cells through ATP-binding cassette transporter A1.
abstract: High-density lipoprotein (HDL) can induce cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release in endothelial cells to exert multiple antiatherogenic functions. This effect has been attributed mainly to the role of sphingosine-1-phosphate (S1P) integrated in HDL. However, whether apolipoprotein A-I (apoA-I), the major apolipoprotein of HDL, could induce COX-2 expression and PGI-2 release still remains unclear. In the present study, we selectively delipidated HDL and confirmed that apoA-I could facilitate COX-2 expression and PGI-2 production in human umbilical vein endothelial cells (HUVECs). ApoA-I, but not trypsinized apoA-I, induced COX-2 expression in a time- and dose-dependent manner consistent with a key role for apoA-I in this process. Additionally, cotreatment of apoA-I with S1P further enhanced COX-2 expression and PGI-2 production in HUVECs. These effects triggered by apoA-I were not inhibited by pertussis toxin, consistent with SIP receptor independent pathway for apoA-I effect. Moreover, we demonstrated that the activation of p38 mitogen-activated protein kinase (MAPK), extracellular receptor kinase (ERK) 1/2, and JAK2 pathways by apoA-I was involved in the expression of COX-2 and the release of PGI-2 in HUVECs, and these effects were inhibited by their specific inhibitors, respectively. Small interfering RNA experiments showed that ATP binding-cassette transporter A1 (ABCA1) was required for COX-2 expression and PGI-2 release induced by apoA-I. Thus our results indicate that apoA-I induces COX-2 expression and PGI-2 release through ABCA1 and the activation of intracellular p38 MAPK, ERK1/2, as well as JAK2 pathways, and apoA-I can reinforce these effects with S1P in HUVECs. These novel effects of apoA-I could in part mediate antiatherogenic effects of HDL.
authors: The Institute of Cardiovascular Sciences, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Peking Univ. Health Science Center, Haidian District, Beijing, China.
authors: Donghui
authors: D
authors: Liu
authors: Liang
authors: L
authors: Ji
authors: Xunliang
authors: X
authors: Tong
authors: Bing
authors: B
authors: Pan
authors: Jing-Yan
authors: JY
authors: Han
authors: Yining
authors: Y
authors: Huang
authors: Y Eugene
authors: YE
authors: Chen
authors: Subramaniam
authors: S
authors: Pennathur
authors: Youyi
authors: Y
authors: Zhang
authors: Lemin
authors: L
authors: Zheng
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D001053:Apolipoproteins / Q000032:analysis; D002478:Cells, Cultured; D002784:Cholesterol / Q000032:analysis; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D011464:Epoprostenol / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000032:analysis; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000494:pharmacology; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D010743:Phospholipids / Q000032:analysis / Q000302:isolation & purification / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014357:Trypsin / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; C505693:APOA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001053:Apolipoproteins; D005230:Fatty Acids, Nonesterified; D005419:Flavonoids; D007093:Imidazoles; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D010743:Phospholipids; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D034741:RNA, Small Interfering; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C060506:sphingosine 1-phosphate; D002784:Cholesterol; D011464:Epoprostenol; D051546:Cyclooxygenase 2; D037342:Pertussis Toxin; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014357:Trypsin; D013110:Sphingosine; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one