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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
ATP Binding Cassette Transporter 1
-
ATP-Binding Cassette Transporters / genetics
-
ATP-Binding Cassette Transporters / metabolism*
-
Apolipoprotein A-I / analysis
-
Apolipoprotein A-I / isolation & purification
-
Apolipoprotein A-I / metabolism
-
Apolipoprotein A-I / pharmacology*
-
Apolipoproteins / analysis
-
Cells, Cultured
-
Cholesterol / analysis
-
Cyclooxygenase 2 / metabolism*
-
Down-Regulation / drug effects
-
Down-Regulation / genetics
-
Drug Synergism
-
Epoprostenol / metabolism*
-
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
-
Extracellular Signal-Regulated MAP Kinases / metabolism
-
Fatty Acids, Nonesterified / analysis
-
Flavonoids / pharmacology
-
Gene Expression / drug effects*
-
Human Umbilical Vein Endothelial Cells / drug effects
-
Human Umbilical Vein Endothelial Cells / metabolism*
-
Humans
-
Imidazoles / pharmacology
-
Janus Kinase 2 / antagonists & inhibitors
-
Janus Kinase 2 / metabolism
-
Lipoproteins, HDL / chemistry
-
Lipoproteins, HDL / pharmacology
-
Lysophospholipids / antagonists & inhibitors
-
Lysophospholipids / pharmacology
-
Pertussis Toxin / pharmacology
-
Phospholipids / analysis
-
Phospholipids / isolation & purification
-
Phospholipids / pharmacology
-
Phosphorylation / drug effects
-
Protein Kinase Inhibitors / pharmacology
-
Pyridines / pharmacology
-
RNA, Small Interfering / genetics
-
Signal Transduction / drug effects
-
Signal Transduction / physiology
-
Sphingosine / analogs & derivatives
-
Sphingosine / antagonists & inhibitors
-
Sphingosine / pharmacology
-
Trypsin / metabolism
-
Tyrphostins / pharmacology
-
Up-Regulation / drug effects
-
Up-Regulation / genetics
-
p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
-
p38 Mitogen-Activated Protein Kinases / metabolism
Substances
-
ABCA1 protein, human
-
APOA1 protein, human
-
ATP Binding Cassette Transporter 1
-
ATP-Binding Cassette Transporters
-
Apolipoprotein A-I
-
Apolipoproteins
-
Fatty Acids, Nonesterified
-
Flavonoids
-
Imidazoles
-
Lipoproteins, HDL
-
Lysophospholipids
-
Phospholipids
-
Protein Kinase Inhibitors
-
Pyridines
-
RNA, Small Interfering
-
Tyrphostins
-
alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
-
sphingosine 1-phosphate
-
Cholesterol
-
Epoprostenol
-
Cyclooxygenase 2
-
Pertussis Toxin
-
JAK2 protein, human
-
Janus Kinase 2
-
Extracellular Signal-Regulated MAP Kinases
-
p38 Mitogen-Activated Protein Kinases
-
Trypsin
-
Sphingosine
-
SB 203580
-
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one