Oxidative modification of LDL is an important, if not obligatory, step that mediates the atherogenicity of LDL. Many pathological conditions and environmental factors promote LDL oxidation, especially formation of early forms of oxidized LDL, termed minimally modified LDL (mmLDL). In addition to established presence of oxidized LDL in atherosclerotic lesions, recent reports find early oxidized forms of LDL even in the blood of apparently healthy individuals, and elevated levels in people with cardiovascular disease. This proposal will examine my hypothesis that mmLDL promotes inflammation in atherosclerotic lesions via modulation of Toll-like receptor (TLR) signaling. This hypothesis has been supported by our recently published findings that mmLDL, but not extensively oxidized LDL, binds to CD14 and that this complex activates TLR4, resulting in cytoskeletal rearrangements and pro-inflammatory signaling and cytokine expression. In addition, our preliminary data demonstrate that mmLDL augments LPS-induced cytokine secretion by macrophages in vitro. CD14 and TLR4 are crucial innate immune receptors that sense bacterial LPS. The existence of mmLDL signaling through CD14/TLR4 suggests convergence of immune responses to oxidation-specific self-antigens and to microbial pathogens. I propose the following Specific Aims for this project: 1) To test the hypothesis that mmLDL induces specific clustering of TLR4 with other receptors on the surface of macrophages, thereby initiating a unique intracellular signaling cascade. 2) To test the hypothesis that a unique set of pro-inflammatory genes expressed and secreted in response to mmLDL is a result of a crosstalk between TLR4-dependent and independent signaling pathways. 3) To test the hypothesis that mmLDL augments pro-inflammatory gene expression induced by LPS and other TLR ligands in animal models of inflammation. 4) To test the hypothesis that mmLDL promotes TLR-dependent inflammation in atherosclerotic lesions. Further development of my hypothesis will help elucidate mechanisms of chronic inflammation in development of atherosclerosis and better understand how particular microbial pathogens increase the risk of atherosclerotic complications. Because the oxidized moieties in mmLDL are likely to be common components of oxidized membranes in general, these studies are likely to have generalized importance. ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Wassef, Momtaz K
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University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Miller, Yury I; Shyy, John Y-J (2017) Context-Dependent Role of Oxidized Lipids and Lipoproteins in Inflammation. Trends Endocrinol Metab 28:143-152
Choi, Soo-Ho; Wiesner, Philipp; Almazan, Felicidad et al. (2012) Spleen tyrosine kinase regulates AP-1 dependent transcriptional response to minimally oxidized LDL. PLoS One 7:e32378
Miller, Yury I; Choi, Soo-Ho; Wiesner, Philipp et al. (2012) The SYK side of TLR4: signalling mechanisms in response to LPS and minimally oxidized LDL. Br J Pharmacol 167:990-9
Miller, Yury I; Choi, Soo-Ho; Wiesner, Philipp et al. (2011) Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res 108:235-48
Ley, Klaus; Miller, Yury I; Hedrick, Catherine C (2011) Monocyte and macrophage dynamics during atherogenesis. Arterioscler Thromb Vasc Biol 31:1506-16
Schoppee Bortz, Pamela D; Wamhoff, Brian R (2011) Chromatin immunoprecipitation (ChIP): revisiting the efficacy of sample preparation, sonication, quantification of sheared DNA, and analysis via PCR. PLoS One 6:e26015
Fang, Longhou; Harkewicz, Richard; Hartvigsen, Karsten et al. (2010) Oxidized cholesteryl esters and phospholipids in zebrafish larvae fed a high cholesterol diet: macrophage binding and activation. J Biol Chem 285:32343-51
Wiesner, Philipp; Choi, Soo-Ho; Almazan, Felicidad et al. (2010) Low doses of lipopolysaccharide and minimally oxidized low-density lipoprotein cooperatively activate macrophages via nuclear factor kappa B and activator protein-1: possible mechanism for acceleration of atherosclerosis by subclinical endotoxemia. Circ Res 107:56-65
Miller, Yury I; Choi, Soo-Ho; Fang, Longhou et al. (2010) Lipoprotein modification and macrophage uptake: role of pathologic cholesterol transport in atherogenesis. Subcell Biochem 51:229-51
Choi, Soo-Ho; Harkewicz, Richard; Lee, Jee Hyun et al. (2009) Lipoprotein accumulation in macrophages via toll-like receptor-4-dependent fluid phase uptake. Circ Res 104:1355-63

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