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  1. N. M. Gharavi1,2,
  2. P. S. Gargalovic1,3,
  3. I. Chang1,
  4. J. Araujo1,
  5. A. D. Watson1,
  6. A. J. Lusis1,3,
  7. J. A. Berliner1,2
  1. 1Department of Medicine, Division of Cardiology
  2. 2Department of Pathology
  3. 3Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA.


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 (EC) to induce a complex inflammatory response. Previously, we demonstrated induction of genes regulating chemotaxis, sterol biosynthesis, the unfolded protein response, and redox homeostasis by Ox-PAPC in human aortic EC (HAEC). Activation of the c-Src kinase/STAT3 pathway and the endothelial nitric oxide synthase (eNOS)/sterol regulatory element binding protein (SREBP) pathway were shown to regulate several of these inflammatory effects of Ox-PAPC in HAEC. High-density lipoprotein (HDL) has anti-inflammatory and antioxidant properties. The goal of the current studies was to determine the role of HDL in regulating Ox-PAPC signaling in HAEC. Using quantitative real-time PCR and Western analysis, we demonstrated that pretreatment of HAEC with HDL for 1 hour, followed by cotreatment, reduced the induction of chemotactic, sterol biosynthetic and UPR genes, by Ox-PAPC and PEIPC. Furthermore, treatment with HDL inhibited the activation of c-Src kinase, STAT3, and SREBP and reversed the uncoupling of eNOS triggered by Ox-PAPC. Finally, we demonstrated that treatment with HDL did not inhibit Ox-PAPC and PEIPC activation of redox pathways, which protect the cell from the effects of oxidative stress. Taken together, these studies demonstrated that HDL inhibits the proinflammatory effects of Ox-PAPC and PEIPC while maintaining the antioxidant activities of these oxidized lipids.

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