High-density lipoprotein modulates oxidized phospholipid signaling in human endothelial cells from proinflammatory to anti-inflammatory.
OBJECTIVE
Oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycero-phosphorylcholine (Ox-PAPC) and its component phospholipid, 1-palmitoyl-2-(5,6 epoxyisoprostanoyl)-sn-glycero-3-phosphocholine (PEIPC), which are present in atherosclerotic lesions, activate endothelial cells to induce a complex inflammatory and pro-oxidant response. Previously, we demonstrated induction of genes regulating chemotaxis, sterol biosynthesis, the unfolded protein response, and redox homeostasis by Ox-PAPC in human aortic endothelial cells (HAECs). Activation of the c-Src kinase/signal transducer and activator of transcription 3 and the endothelial nitric oxide synthase/sterol regulatory element binding protein (SREBP) pathways were shown to regulate several of these inflammatory effects of Ox-PAPC in HAECs. The goal of the current studies was to determine the role of high-density lipoprotein (HDL) in regulating Ox-PAPC signaling in HAECs.


RESULTS
Using quantitative real-time polymerase chain reaction, Western analysis, and functional studies, we demonstrated that pretreatment of HAECs with HDL reduced the induction of inflammatory, sterol biosynthetic, and unfolded protein response genes by Ox-PAPC and PEIPC; Ox-PAPC-induced chemotactic activity and monocyte binding were also decreased. These effects were associated with HDL inhibition of Ox-PAPC-induced c-Src, signal transducer and activator of transcription 3, and SREBP activation, alterations in endothelial nitric oxide synthase phosphorylation (previously associated with the inflammatory action of Ox-PAPC), and a decrease in superoxide formation. Finally, we demonstrated that treatment with HDL did not inhibit Ox-PAPC and PEIPC-induced activation of redox pathways, which protect the cell from the effects of oxidative stress.


CONCLUSIONS
Taken together, these studies demonstrated that HDL inhibits the pro-inflammatory effects of Ox-PAPC and PEIPC, while maintaining the antioxidant activities of these lipids.
Gharavi
Nima M
NM
Department of Medicine, University of California, Los Angeles, Calif, USA.
Gargalovic
Peter S
PS
Chang
Irene
I
Araujo
Jesus A
JA
Clark
Michael J
MJ
Szeto
Wan Lam
WL
Watson
Andrew D
AD
Lusis
Aldons J
AJ
Berliner
Judith A
JA
D000893:Anti-Inflammatory Agents / Q000378:metabolism* / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism; D000081247:CSK Tyrosine-Protein Kinase; D002448:Cell Adhesion; D002478:Cells, Cultured; D002633:Chemotaxis; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D028421:Isoprostanes / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010713:Phosphatidylcholines / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism; D013261:Sterols / Q000096:biosynthesis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases
C500237:1-palmitoyl-2-(epoxyisoprostane-E2)-sn-glycero-3-phosphocholine; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016207:Cytokines; D028421:Isoprostanes; D008075:Lipoproteins, HDL; D010713:Phosphatidylcholines; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D051779:Sterol Regulatory Element Binding Proteins; D013261:Sterols; D014157:Transcription Factors; C472349:oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human