title: HDL promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells.
abstract: HDL cholesterol (HDL-C) plasma levels are inversely related to cardiovascular disease risk. Previous studies have shown in animals and humans that HDL promotes regression of atherosclerosis. We hypothesized that this was related to an ability to promote the loss of monocyte-derived cells (CD68(+), primarily macrophages and macrophage foam cells) from plaques. To test this hypothesis, we used an established model of atherosclerosis regression in which plaque-bearing aortic arches from apolipoprotein E-deficient (apoE(-/-)) mice (low HDL-C, high non-HDL-C) were transplanted into recipient mice with differing levels of HDL-C and non-HDL-C: C57BL6 mice (normal HDL-C, low non-HDL-C), apoAI(-/-) mice (low HDL-C, low non-HDL-C), or apoE(-/-) mice transgenic for human apoAI (hAI/apoE(-/-); normal HDL-C, high non-HDL-C). Remarkably, despite persistent elevated non-HDL-C in hAI/apoE(-/-) recipients, plaque CD68(+) cell content decreased by >50% by 1 wk after transplantation, whereas there was little change in apoAI(-/-) recipient mice despite hypolipidemia. The decreased content of plaque CD68(+) cells after HDL-C normalization was associated with their emigration and induction of their chemokine receptor CCR7. Furthermore, in CD68(+) cells laser-captured from the plaques, normalization of HDL-C led to decreased expression of inflammatory factors and enrichment of markers of the M2 (tissue repair) macrophage state. Again, none of these beneficial changes were observed in the apoAI(-/-) recipients, suggesting a major requirement for reverse cholesterol transport for the beneficial effects of HDL. Overall, these results establish HDL as a regulator in vivo of the migratory and inflammatory properties of monocyte-derived cells in mouse atherosclerotic plaques, and highlight the phenotypic plasticity of these cells.
authors.affiliation: The Leon H. Charney Division of Cardiology, Department of Medicine, The Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Feig
authors.forename: James X
authors.initials: JX
authors.lastname: Rong
authors.forename: Raanan
authors.initials: R
authors.lastname: Shamir
authors.forename: Marie
authors.initials: M
authors.lastname: Sanson
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Vengrenyuk
authors.forename: Jianhua
authors.initials: J
authors.lastname: Liu
authors.forename: Katey
authors.initials: K
authors.lastname: Rayner
authors.forename: Kathryn
authors.initials: K
authors.lastname: Moore
authors.forename: Michael
authors.initials: M
authors.lastname: Garabedian
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism; D001011:Aorta / Q000378:metabolism / Q000637:transplantation; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008076:Cholesterol, HDL / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D054400:Receptors, CCR7; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C515371:Ccr7 protein, mouse