Atherosclerosis is an inflammatory process characterized by accumulation of lipid-laden macrophages/ dendritic cells (DCs) (foam cells) in arterial walls. Hypercholesterolemia with increased levels of cholesteryl ester-rich lipoproteins (CERLs) has long been recognized as a risk factor for atherogenesis. Recent genetic and epidemiologic studies show that triglyceride-rich lipoproteins (TGRLs) also play an important role in atherosclerosis. While previous studies have focused on interactions of CERLs with tissue macrophages, infiltration of blood monocytes into tissues and differentiation to macrophages/DCs is a key step in inflammation including atherogenesis. With the recent identification of monocyte heterogeneity and plasticity, studies have shown that monocytes with different phenotypes play distinct roles in inflammation. However, effects of CERLs on blood monocyte phenotype and subsequent impacts on monocyte contribution to atherogenesis have not been well studied and effects of TGRLs on monocytes and the consequence to atherogenesis are even less well studied. We previously reported that mice with hypercholesterolemia and humans with hypertriglyceridemia had foamy monocytes, i.e., monocytes with intracellular lipid droplets, in blood. Our further preliminary studies showed that monocytes took up CERLs and TGRLs (becoming foamy monocytes) and subsequently underwent phenotypic changes, with increased expression of: 1) proinflammatory markers; 2) the adhesion molecule CD11c, which enhanced monocyte adhesion on endothelial cells (ECs); and 3) scavenger receptors that promoted further monocyte uptake of CERLs and foam cell formation. Based on these data, we formed our central hypothesis that in hyperlipidemia, blood monocytes take up TGRLs and/or CERLs and undergo phenotypic changes, with increased inflammation, enhanced adhesion to ECs and increased uptake of CERLs, which accelerate monocyte infiltration into arterial walls, differentiation into macrophages/DCs and foam cell formation, thereby contributing to atherogenesis. In this application, we will use in vitro tissue culture, in vivo mouse models and human subjects to examine how blood monocytes take up TGRLs and CERLs and change phenotypes and determine how these phenotypically changed monocytes infiltrate into arterial walls and contribute to atherogenesis. For our approach, we will use some unique protocols such as specific labeling and depletion of foamy monocytes in mouse models of atherosclerosis and microfluidic-based lab-chip assays, as well as other techniques such as flow cytometric analysis, immunofluorescent staining, Luminex technology, microarray and NanoString systems. Our approach will not only further our understanding of the mechanisms for atherogenesis but may also help identify novel therapeutic targets for atherosclerotic cardiovascular disease.

Public Health Relevance

High blood levels of lipids, including cholesterol and triglyceride, increase the risk for atherosclerotic cardiovascular disease. Our project proposes to study effects of blood lipids (lipoproteins) on phenotypes and behaviors of blood monocytes, with subsequent impact on monocyte contribution to the development of atherosclerosis. Knowledge gained from our studies may help identify novel therapeutic targets to prevent cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098839-06
Application #
9034653
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Hasan, Ahmed AK
Project Start
2009-12-01
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Wang, Qun; Wu, Huaizhu (2018) T Cells in Adipose Tissue: Critical Players in Immunometabolism. Front Immunol 9:2509
Dai Perrard, Xiao-Yuan; Lian, Zeqin; Bobotas, George et al. (2017) Effects of n-3 fatty acid treatment on monocyte phenotypes in humans with hypertriglyceridemia. J Clin Lipidol 11:1361-1371
Wu, Huaizhu; Ballantyne, Christie M (2017) Skeletal muscle inflammation and insulin resistance in obesity. J Clin Invest 127:43-54
Aziz, Moammir H; Cui, Kui; Das, Mitali et al. (2017) The Upregulation of Integrin ?D?2 (CD11d/CD18) on Inflammatory Macrophages Promotes Macrophage Retention in Vascular Lesions and Development of Atherosclerosis. J Immunol 198:4855-4867
Wu, Huaizhu; Ballantyne, Christie M (2017) Dyslipidaemia: PCSK9 inhibitors and foamy monocytes in familial hypercholesterolaemia. Nat Rev Cardiol 14:385-386
Zhou, Hao; Ran, Yali; Da, Qi et al. (2016) Defective Association of the Platelet Glycoprotein Ib-IX Complex with the Glycosphingolipid-Enriched Membrane Domain Inhibits Murine Thrombus and Atheroma Formation. J Immunol 197:288-95
Lin, Ligen; Lee, Jong Han; Buras, Eric D et al. (2016) Ghrelin receptor regulates adipose tissue inflammation in aging. Aging (Albany NY) 8:178-91
Khan, Ilvira M; Pokharel, Yashashwi; Dadu, Razvan T et al. (2016) Postprandial Monocyte Activation in Individuals With Metabolic Syndrome. J Clin Endocrinol Metab 101:4195-4204
Khan, I M; Perrard, X Yd; Brunner, G et al. (2015) Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance. Int J Obes (Lond) 39:1607-18
Xu, Lu; Dai Perrard, Xiaoyuan; Perrard, Jerry L et al. (2015) Foamy monocytes form early and contribute to nascent atherosclerosis in mice with hypercholesterolemia. Arterioscler Thromb Vasc Biol 35:1787-97

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