Vascular inflammation is recognized as a critical process in the initiation, progression and complications of insulin resistance, type 2 diabetes, and atherosclerosis. Toll-like receptors (TLRs) are traditionally described as cellular sensors for microbial pathogens, but more recently demonstrated by us and others to recognize modified (e.g. oxidized) host molecules, leading to TLR-mediated inflammatory responses by vascular cells. Human epidemiologic and animal experimental studies have implicated TLR4 in the development of insulin resistance, diabetes and atherosclerosis. Work from our lab has shown that in macrophages, TLR4 signaling is activated by minimally oxidized LDL (mmLDL), an early form of oxidized LDL found in atherosclerotic lesions. In addition, TLR4 is activated by lipopolysaccharide (LPS), the prototypical bacterial endotoxin, and emerging evidence suggests that persistent subclinical endotoxemia is an integral component of metabolic disorders induced by Western type, high-fat diets, and has been termed """"""""metabolic endotoxemia"""""""". We have demonstrated that injections of low doses of LPS and mmLDL cooperatively (and even synergistically) activate macrophages in a TLR4-dependent manner to express higher levels of proinflammatory cytokines. In this grant proposal, we will test the hypothesis that metabolic endotoxemia, induced by a high-fat diet, together with oxidized lipids, components of mmLDL, synergistically enhance vascular inflammation. These experiments will help elucidate mechanisms of accelerated atherosclerosis in obese and diabetic patients. Specifically, we will study oxidized cholesteryl esters (OxCE), produced in LDL as a result of oxidative modification by 12/15-lipoxygenase (12/15LO). 12/15LO is a major enzyme that promotes LDL oxidation In vivo, and has been implicated in the onset of adipose tissue inflammation and insulin resistance, development of diabetic vasculopathy and atherosclerosis. We have identified CE oxidized via 12/15LO catalysis as active components of mmLDL responsible for TLR4-dependent proinflammatory effects in macrophages. Importantly, we have shown the presence of such OxCE in murine atherosclerotic lesions. In this application, we will study In vivo vascular inflammation induced by cooperative stimulation with mmLDL, OxCE and endogenous 12/15LO activity, on the one hand, and metabolic endotoxemia on the other. Moreover, we will utilize mass spectrometry techniques and OxCE-specific antibodies to provide evidence for the importance of OxCE in pathophysiological processes, and for development of novel biomarker and imaging applications.

Public Health Relevance

Atherosclerosis is a vascular inflammatory disease, manifesting in myocardial infarction and stroke, which are leading causes of mortality and morbidity. In this project, we will consider metabolic endotoxemia, which is characteristic for obese and diabetic patients, and oxidized lipids, which are important pro-atherogenic molecules, and will elucidate their cooperative effects in vascular inflammation. Understanding the mechanisms of vascular inflammation and introducing new biomarker and cardiovascular imaging approaches will significantly advance developing new therapeutic strategies for treatment of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL055798-16A1
Application #
8396684
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M1))
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
16
Fiscal Year
2012
Total Cost
$502,328
Indirect Cost
$18,500
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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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
Torzewski, Michael; Ravandi, Amir; Yeang, Calvin et al. (2017) Lipoprotein(a) Associated Molecules are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis. JACC Basic Transl Sci 2:229-240
Kamstrup, Pia R; Hung, Ming-Yow; Witztum, Joseph L et al. (2017) Oxidized Phospholipids and Risk of Calcific Aortic Valve Disease: The Copenhagen General Population Study. Arterioscler Thromb Vasc Biol 37:1570-1578
Ley, Klaus; Gerdes, Norbert; Winkels, Holger (2017) ATVB Distinguished Scientist Award: How Costimulatory and Coinhibitory Pathways Shape Atherosclerosis. Arterioscler Thromb Vasc Biol 37:764-777
Yeang, Calvin; Gordts, Philip L S M; Tsimikas, Sotirios (2017) Novel Lipoprotein(a) Catabolism Pathway via Apolipoprotein(a) Recycling: Adding the Plasminogen Receptor PlgRKT to the List. Circ Res 120:1050-1052
Pechlaner, Raimund; Tsimikas, Sotirios; Yin, Xiaoke et al. (2017) Very-Low-Density Lipoprotein-Associated Apolipoproteins Predict Cardiovascular Events and Are Lowered by Inhibition of APOC-III. J Am Coll Cardiol 69:789-800
Lee, Sang-Rok; Prasad, Anand; Choi, Yun-Seok et al. (2017) LPA Gene, Ethnicity, and Cardiovascular Events. Circulation 135:251-263
Nowyhed, Heba N; Chandra, Shilpi; Kiosses, William et al. (2017) ATP Binding Cassette Transporter ABCA7 Regulates NKT Cell Development and Function by Controlling CD1d Expression and Lipid Raft Content. Sci Rep 7:40273
Choi, Soo-Ho; Sviridov, Dmitri; Miller, Yury I (2017) Oxidized cholesteryl esters and inflammation. Biochim Biophys Acta 1862:393-397

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