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.
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.
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|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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