The ultimate treatment for coronary artery disease is the regression of the underlying atherosclerotic process. We have developed a novel mouse model for the study of regression in which plaques that developed into apoE-/- mice (high plasma non-HDL cholesterol (C), low HDL-C, absent apoE) are transplanted into wild type (WT) mice, which have low non-HDL-C, normal HDL-C, and normal apoE in their plasma. We have found that in the WT plasma environment, there is remarkable remodeling of the transplanted plaques over a relatively short time, with depletion of the majority of CD68+ cells (which are primarily macrophages and foam cells). Previous studies in WT recipients showed that the depletion of CD68+ cells reflected their emigration to lymph nodes, and required the upregulation of their chemokine receptor CCR7, a known migratory factor in monocyte-derived cells. Furthermore, the phenotypic state of the CD68+ cells shifted from an inflammatory ("M1") to an anti-inflammatory one ("M2"). We hypothesize that each of the 3 plasma changes in the WT recipient contributes to the migratory and inflammatory properties of plaque CD68+ cells during regression. Because each plasma change promotes reverse cholesterol transport (RCT), a related hypothesis is that deficiency in macrophage RCT will compromise the ability of a plasma factor to influence CD68+ cell emigration and polarization to the M2 state. Two other hypotheses are that the transcriptional regulation of the migration factor CCR7 is regulated by the nuclear hormone receptor LXR and the sterol-regulated SREBP pathway (based on preliminary studies), and that the identification of the molecular processes central to the regression process in plaque CD68+ cells requires a systems biology approach that includes the meta- analyses of microarray and proteomic data across in vivo and in vitro studies. To test these hypotheses, there are 3 aims.
Aim 1 : To establish the roles of changes in plasma non-HDL-C, HDL-C, and apoE, and of RCT in atherosclerosis regression and phenotypic changes in plaque CD68+ cells;
Aim 2 : To determine the roles of LXR and SREBP in regulating CCR7 expression in vitro and in vivo;
Aim 3 : To employ a systems biology approach to identify the key molecular drivers of regression.
The complications of atherosclerosis, coronary artery and cerebrovascular diseases, are major killers of the American population. Despite valuable benefits from current therapeutics, there is still considerable residual risk to the population. Learning more about how atherosclerotic plaques regress will likely lead to new therapeutic and diagnostic clinical strategies.
|Iqbal, Asif J; Fisher, Edward A; Greaves, David R (2016) Inflammation-a Critical Appreciation of the Role of Myeloid Cells. Microbiol Spectr 4:|
|Fisher, Edward A (2016) Regression of Atherosclerosis: The Journey From the Liver to the Plaque and Back. Arterioscler Thromb Vasc Biol 36:226-35|
|Zhang, Xue-Qing; Even-Or, Orli; Xu, Xiaoyang et al. (2015) Nanoparticles containing a liver X receptor agonist inhibit inflammation and atherosclerosis. Adv Healthc Mater 4:228-36|
|Vengrenyuk, Yuliya; Nishi, Hitoo; Long, Xiaochun et al. (2015) Cholesterol loading reprograms the microRNA-143/145-myocardin axis to convert aortic smooth muscle cells to a dysfunctional macrophage-like phenotype. Arterioscler Thromb Vasc Biol 35:535-46|
|Ouimet, Mireille; Ediriweera, Hasini N; Gundra, U Mahesh et al. (2015) MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J Clin Invest 125:4334-48|
|Miller, Miles A; Gadde, Suresh; Pfirschke, Christina et al. (2015) Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle. Sci Transl Med 7:314ra183|
|Wu, Chaowei; Hussein, Maryem A; Shrestha, Elina et al. (2015) Modulation of Macrophage Gene Expression via Liver X Receptor Î± Serine 198 Phosphorylation. Mol Cell Biol 35:2024-34|
|Menon, Prashanthi; Fisher, Edward A (2015) Immunostaining of Macrophages, Endothelial Cells, and Smooth Muscle Cells in the Atherosclerotic Mouse Aorta. Methods Mol Biol 1339:131-48|
|Kuan, Emma L; Ivanov, Stoyan; Bridenbaugh, Eric A et al. (2015) Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells. J Immunol 194:5200-10|
|Williams, Kevin Jon; Tabas, Ira; Fisher, Edward A (2015) How an artery heals. Circ Res 117:909-13|
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