Subbanagounder, G. et al. Epoxyisoprostane and epoxycyclopentenone phospholipids regulate monocyte chemotactic protein-1 and interleukin-8 synthesis. Formation of these oxidized phospholipids in response to interleukin-1. J. Biol. Chem. 277, 7271-7281

Department of Medicine, University of California, Los Angeles, Los Ángeles, California, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2002; 277(9):7271-81. DOI: 10.1074/jbc.M107602200
Source: PubMed


Monocyte recruitment to the vessel wall, mediated by monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8), plays an important role in atherogenesis. We have shown previously that minimally oxidized low density lipoprotein, oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (Ox-PAPC), activates endothelial cells to produce MCP-1 and IL-8. By using liquid chromatography/mass spectrometry methods coupled with bioassay, we report a family of epoxyisoprostane (PEIPC) and epoxycyclopentenone (PECPC) phospholipids that are the components of Ox-PAPC responsible for the majority of this activity. Ox-PAPC contains five chromatographically distinguishable active PEIPC components (m/z 825.5) and four PECPC components (m/z 810.5). All nine components induced endothelial cell synthesis of IL-8 and MCP-1 in a dose-dependent fashion between 0.1 and 5 microm concentrations. The five PEIPC components had identical functional groups and all underwent dehydration to produce m/z 810.5. We present evidence that these phospholipids are regioisomers with epoxide groups at the 5,6-, 8,9-, 11,12-, or 14,15-positions of the sn-2 fatty acid and their epoxide groups is important for biological activity. We have shown previously that peroxisome proliferator-activated receptor alpha is involved in MCP-1 synthesis in response to Ox-PAPC. We now show that PEIPC and PECPC isomers are potent activators of peroxisome proliferator-activated receptor alpha. PEIPC and PECPC isomers are strongly recognized by specific circulating murine natural autoantibodies (EO6) and accumulate in cells treated with IL-1beta. These studies demonstrate that PEIPC and PECPC isomers are potent activators of endothelial cells increasing synthesis of IL-8 and MCP-1. Their accumulation in cells exposed to cytokines and in atherosclerotic lesions suggests that these lipids may play a role in a number of chronic disease processes.

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    • "Different PLA2 has been shown to be associated with the development of atherosclerosis. We previously showed that the removal of the structure at sn-2 position of oxidized lipid by PLA2 abolished several inflammatory effects of OxPAPC component lipids [9] [10]. "
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    ABSTRACT: Atherosclerosis is the main underlying cause of major cardiovascular diseases such as stroke and heart attack. Oxidized phospholipids such as oxidized 1-palmitoyl-2-arachidonoyl-sn-Glycero-3-phosphorylcholine (OxPAPC) accumulate in lesions of and promote atherosclerosis. OxPAPC activates endothelial cells, a critical early event of atherogenesis. Epoxyisoprostane E2 (EI) is an oxidized fatty acid contained at the sn-2 position of 1-palmitoyl-2-epoxyisoprostane E2-sn-glycero-3-phosphorylcholine (PEIPC), the most active component of OxPAPC in regulating inflammation. OxPAPC and its components including PEIPC activate endothelial cells to express an array of genes in different categories including oxidative stress response genes such as tumor suppressor gene OKL38 and Hemeoxygenase-1 (HO-1). EI can be released by lipase from PEIPC. In this study, we examined the ability of EI to stimulate oxidative stress response in endothelial cells. EI released from OxPAPC and synthetic EI stimulated the expression of oxidative stress response gene OKL38 and antioxidant gene HO-1. Treatment of endothelial cells with EI increased the production of superoxide. NADPH oxidase inhibitor Apocynin and superoxide scavenger N-acetyl-cysteine (NAC) significantly attenuated EI-stimulated expression of OKL38 and HO-1. We further demonstrated that EI activated oxidative stress-sensitive transcription factor Nrf2. Silencing of Nrf2 with siRNA significantly reduced EI stimulated expression of OKL38 and HO-1. Thus, we demonstrated that EI induced oxidative stress in endothelial cells leading to increased expression of oxidative stress response gene OKL38 and HO-1 via Nrf2 signaling pathway relevant to atherosclerosis.
    Full-text · Article · Jan 2014 · Biochemical and Biophysical Research Communications
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    • "PEIPC was detected at high levels in atherosclerotic lesions of cholesterol-fed rabbits, 60–100 μg/g of wet tissue weight [13, 16]. PEIPC and PECPC are potent activators of endothelial cells, increasing synthesis of IL-8 and MCP-1, and are also concentrated within atherosclerotic lesions [10, 11, 31, 41]. "
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    ABSTRACT: Oxidized PLs (OxPLs) generated in health and disease are now recognized as important mediators of cellular signalling. There is an increasing body of evidence showing that PL peroxidation is not only increased in vascular disorders, but is also a physiological event of relevance to coagulation, innate immunity, and self-tolerance. Nonenzymatically formed OxPLs generated during chronic inflammation is an uncontrolled event, generating hundreds of diverse structures, and prone to more deleterious bioactivities. In contrast, enzymatic formation of OxPLs is tightly regulated, involving receptors and intracellular signaling, acting as part of the normal physiological response to injury in order to restore homeostasis. In the present review, the major nonenzymatic OxPLs structures found during vascular inflammation are summarized, along with a brief description of their known biological activities. Also, we review what is currently known about enzymatic formation of OxPLs by acutely activated immune cells and their signaling actions under homeostatic and pathological conditions.
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    • "Monocyte chemoattractant protein 1/Chemokine (C-C motif) ligand 2 (MCP-1/CCL2) and its receptor, CC-chemokine receptor 2 (CCR2), are noted to play an important role in the initiation of atherosclerosis, probably due to the increased monocyte and T-cell attraction and infiltration into the plaque. Several studies have demonstrated that oxidized low-density lipoprotein (oxLDL) is chemoattractant and that its oxidized phospholipid components can induce endothelial activation as judged by upregulated expression of MCP-1 [22] [23]. Other chemokines are also detected in atherosclerotic plaques, such as the cell-surface anchored CX3-chemokine ligand 1 (CX3CL1), which is expressed on vascular smooth muscle cells. "
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