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.
|Feig, Jonathan E (2014) Regression of atherosclerosis: insights from animal and clinical studies. Ann Glob Health 80:13-23|
|Fisher, Edward A; Miano, Joseph M (2014) Don't judge books by their covers: vascular smooth muscle cells in arterial pathologies. Circulation 129:1545-7|
|Moore, Kathryn J; Fisher, Edward A (2014) High-density lipoproteins put out the fire. Cell Metab 19:175-6|
|Distel, Emilie; Barrett, Tessa J; Chung, Kellie et al. (2014) miR33 inhibition overcomes deleterious effects of diabetes mellitus on atherosclerosis plaque regression in mice. Circ Res 115:759-69|
|Duivenvoorden, Raphaël; Tang, Jun; Cormode, David P et al. (2014) A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation. Nat Commun 5:3065|
|Feig, Jonathan E; Hewing, Bernd; Smith, Jonathan D et al. (2014) High-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical studies. Circ Res 114:205-13|
|Libby, Peter; Tabas, Ira; Fredman, Gabrielle et al. (2014) Inflammation and its resolution as determinants of acute coronary syndromes. Circ Res 114:1867-79|
|Murray, Peter J; Allen, Judith E; Biswas, Subhra K et al. (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41:14-20|
|Ramkhelawon, Bhama; Yang, Yuan; van Gils, Janine M et al. (2013) Hypoxia induces netrin-1 and Unc5b in atherosclerotic plaques: mechanism for macrophage retention and survival. Arterioscler Thromb Vasc Biol 33:1180-8|
|Barazza, Alessandra; Blachford, Courtney; Even-Or, Orli et al. (2013) The complex fate in plasma of gadolinium incorporated into high-density lipoproteins used for magnetic imaging of atherosclerotic plaques. Bioconjug Chem 24:1039-48|
Showing the most recent 10 out of 47 publications