Published online before print March 22, 2007, doi: 10.1161/ATVBAHA.107.141283
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2007 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
High-Density Lipoprotein Modulates Oxidized Phospholipid Signaling in Human Endothelial Cells From Proinflammatory to Anti-inflammatory
From Department of Medicine (N.M.G., P.S.G., I.C., J.A.A., W.L.S., A.D.W., A.J.L., J.A.B.), Department of Pathology (N.M.G., J.A.B.), and Department of Microbiology, Immunology, and Molecular Genetics (P.S.G., M.J.C., A.J.L.), University of California, Los Angeles, Calif.
Correspondence to Dr Judith A Berliner, 13-239 CHS-Pathology, 650 Charles E. Young Drive South, Los Angeles, CA 90095. E-mail jberliner{at}mednet.ucla.edu
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.
Methods and 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.
Previously, we demonstrated that oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycero-phosphorylcholine and component lipids caused induction of genes regulating chemotaxis, sterol biosynthesis, the unfolded protein response, and redox homeostasis in human aortic endothelial cells. Taken together, these studies demonstrated that high-density lipoprotein inhibits the pro-inflammatory effects of oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycero-phosphorylcholine and phospholipid, 1-palmitoyl-2-(5,6 epoxyisoprostanoyl)-sn-glycero-3-phosphocholine, while maintaining the antioxidant activities of these lipids.
Key Words: atherosclerosis • endothelium • inflammation • oxidized phospholipids