Hypercholesterolemia and vascular inflammation are among the strongest causative factors in the development of atherosclerosis and in the progression of early atherosclerotic lesions into advanced vulnerable plaques. However, it is yet unclear whether vascular cholesterol accumulation directly contributes to vascular inflammation and, specifically, to polarization of macrophages into inflammatory phenotypes. In this project, we will investigate two mechanisms, which contribute to cholesterol-mediated inflammatory responses by macrophages, and will determine their quantitative significance in the development of atherosclerosis in a mouse model and the translational potential of relevant new biomarkers and therapeutic approaches. In an atherogenic mechanism, oxidized cholesteryl esters (OxCE) induce dimerization of toll-like receptor-4 (TLR4), which in turn mediates inflammatory and atherogenic responses in macrophages. In an atheroprotective mechanism, we have identified the secreted apoA-I binding protein (AIBP) as a factor, which significantly improves HDL function by accelerating cholesterol efflux, resulting in the disruption of lipid raft-dependent TLR4 dimerization and reduced inflammatory responses in macrophages. We will test the hypotheses that OxCE promotes and AIBP inhibits inflammatory macrophage polarization, foam cell formation and atherosclerosis. We have generated a monoclonal antibody blocking OxCE, as well as systemic and macrophage-specific Apoa1bp-/- mice to test these hypotheses. In complementary experiments, we will use infusions of recombinant AIBP and/or an AIBP-expressing adeno-associated virus to achieve increased AIBP levels in plasma and expect to inhibit atherosclerosis progression. Importantly, synergistic studies with other PPG Projects will examine the relevance of OxCE and AIBP mechanisms to atherogenic or atheroprotective functions of different monocyte and T and B cell populations. To translate our findings into clinic, we will use plasma from Multi-Ethnic Study of Atherosclerosis (MESA) subjects, who have elevated coronary artery calcium or have experienced major adverse cardiovascular events, to evaluate diagnostic and prognostic value of new OxCE and AIBP biomarkers. These results will be integrated with other biomarkers identified by the PPG Investigators. To examine novel therapeutic approaches to restrain cholesterol-induced inflammation, we will test the hypothesis that raising AIBP in the low-AIBP plasma and blocking OxCE in the high-OxCE plasma found in MESA populations will reduce plasma's atherogenic effects on human macrophages. The proposed studies will enhance our mechanistic understanding of cholesterol-mediated inflammation in atherosclerosis and will advance new biomarker and therapeutic strategies for cardiovascular disease.

Public Health Relevance

Inflammatory activation of macrophages in cholesterol-rich atherosclerotic lesions is a major causative factor in the development of vulnerable plaques, whose rupture often leads to heart attack or stroke. This project will investigate disease-promoting and protective mechanisms by which cholesterol regulates macrophages in atherosclerosis. In a large human study, new biomarkers of cardiovascular disease and novel therapeutic strategies will be evaluated.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Chen, Jue
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
La Jolla Institute for Immunology
La Jolla
United States
Zip Code
Prohaska, Thomas A; Que, Xuchu; Diehl, Cody J et al. (2018) Massively Parallel Sequencing of Peritoneal and Splenic B Cell Repertoires Highlights Unique Properties of B-1 Cell Antibodies. J Immunol 200:1702-1717
Kobiyama, Kouji; Vassallo, Melanie; Mitzi, Jessica et al. (2018) A clinically applicable adjuvant for an atherosclerosis vaccine in mice. Eur J Immunol 48:1580-1587
Liu, Chao; Kim, Young Sook; Kim, Jungsu et al. (2018) Modeling hypercholesterolemia and vascular lipid accumulation in LDL receptor mutant zebrafish. J Lipid Res 59:391-399
Schneider, Dina A; Choi, Soo-Ho; Agatisa-Boyle, Colin et al. (2018) AIBP protects against metabolic abnormalities and atherosclerosis. J Lipid Res 59:854-863
Kobiyama, Kouji; Ley, Klaus (2018) Atherosclerosis. Circ Res 123:1118-1120
Woller, Sarah A; Choi, Soo-Ho; An, Eun Jung et al. (2018) Inhibition of Neuroinflammation by AIBP: Spinal Effects upon Facilitated Pain States. Cell Rep 23:2667-2677
Tsimikas, Sotirios (2018) In search of a physiological function of lipoprotein(a): causality of elevated Lp(a) levels and reduced incidence of type 2 diabetes. J Lipid Res 59:741-744
Choi, Soo-Ho; Wallace, Aaron M; Schneider, Dina A et al. (2018) AIBP augments cholesterol efflux from alveolar macrophages to surfactant and reduces acute lung inflammation. JCI Insight 3:
Tsimikas, Sotirios; Fazio, Sergio; Ferdinand, Keith C et al. (2018) NHLBI Working Group Recommendations to Reduce Lipoprotein(a)-Mediated Risk of Cardiovascular Disease and Aortic Stenosis. J Am Coll Cardiol 71:177-192
Liu, Chao; Han, Tianxu; Stachura, David L et al. (2018) Lipoprotein lipase regulates hematopoietic stem progenitor cell maintenance through DHA supply. Nat Commun 9:1310

Showing the most recent 10 out of 16 publications