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.

National Institute of Health (NIH)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
La Jolla Institute
La Jolla
United States
Zip Code
Tsimikas, Sotirios; Duff, Gordon W; Berger, Peter B et al. (2014) Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol 63:1724-34
Willeit, Peter; Kiechl, Stefan; Kronenberg, Florian et al. (2014) Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol 64:851-60
Ai, Ding; Jiang, Hongfeng; Westerterp, Marit et al. (2014) Disruption of mammalian target of rapamycin complex 1 in macrophages decreases chemokine gene expression and atherosclerosis. Circ Res 114:1576-84
Manichaikul, Ani; Rich, Stephen S; Perry, Heather et al. (2014) A functionally significant polymorphism in ID3 is associated with human coronary pathology. PLoS One 9:e90222
Lazic, Milos; Inzaugarat, Maria Eugenia; Povero, Davide et al. (2014) Reduced dietary omega-6 to omega-3 fatty acid ratio and 12/15-lipoxygenase deficiency are protective against chronic high fat diet-induced steatohepatitis. PLoS One 9:e107658
Cheng, Hsin-Yuan; Wu, Runpei; Hedrick, Catherine C (2014) Gammadelta (??) T lymphocytes do not impact the development of early atherosclerosis. Atherosclerosis 234:265-9
Morris-Rosenfeld, Samuel; Lipinski, Michael J; McNamara, Coleen A (2014) Understanding the role of B cells in atherosclerosis: potential clinical implications. Expert Rev Clin Immunol 10:77-89
Fang, Longhou; Liu, Chao; Miller, Yury I (2014) Zebrafish models of dyslipidemia: relevance to atherosclerosis and angiogenesis. Transl Res 163:99-108
Ge, Shuwang; Hertel, Barbara; Koltsova, Ekaterina K et al. (2013) Increased atherosclerotic lesion formation and vascular leukocyte accumulation in renal impairment are mediated by interleukin-17A. Circ Res 113:965-74
Cheng, Hsin-Yuan; Wu, Runpei; Gebre, Abraham K et al. (2013) Increased cholesterol content in gammadelta (ýýýý) T lymphocytes differentially regulates their activation. PLoS One 8:e63746

Showing the most recent 10 out of 141 publications