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Statins promote the regression of atherosclerosis via activation of the CCR7-dependent emigration pathway in macrophages.

Feig, JE; Shang, Y; Rotllan, N; Vengrenyuk, Y; Wu, C; Shamir, R; Torra, IP; ... Garabedian, MJ; + view all (2011) Statins promote the regression of atherosclerosis via activation of the CCR7-dependent emigration pathway in macrophages. PLOS One , 6 (12) , Article e28534. 10.1371/journal.pone.0028534. Green open access

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Abstract

HMG-CoA reductase inhibitors (statins) decrease atherosclerosis by lowering low-density-lipoprotein cholesterol. Statins are also thought to have additional anti-atherogenic properties, yet defining these non-conventional modes of statin action remains incomplete. We have previously developed a novel mouse transplant model of atherosclerosis regression in which aortic segments from diseased donors are placed into normolipidemic recipients. With this model, we demonstrated the rapid loss of CD68+ cells (mainly macrophages) in plaques through the induction of a chemokine receptor CCR7-dependent emigration process. Because the human and mouse CCR7 promoter contain Sterol Response Elements (SREs), we hypothesized that Sterol Regulatory Element Binding Proteins (SREBPs) are involved in increasing CCR7 expression and through this mechanism, statins would promote CD68+ cell emigration from plaques. We examined whether statin activation of the SREBP pathway in vivo would induce CCR7 expression and promote macrophage emigration from plaques. We found that western diet-fed apoE(-/-) mice treated with either atorvastatin or rosuvastatin led to a substantial reduction in the CD68+ cell content in the plaques despite continued hyperlipidemia. We also observed a significant increase in CCR7 mRNA in CD68+ cells from both the atorvastatin and rosuvastatin treated mice associated with emigration of CD68+ cells from plaques. Importantly, CCR7(-/-)/apoE(-/-) double knockout mice failed to display a reduction in CD68+ cell content upon statin treatment. Statins also affected the recruitment of transcriptional regulatory proteins and the organization of the chromatin at the CCR7 promoter to increase the transcriptional activity. Statins promote the beneficial remodeling of plaques in diseased mouse arteries through the stimulation of the CCR7 emigration pathway in macrophages. Therefore, statins may exhibit some of their clinical benefits by not only retarding the progression of atherosclerosis, but also accelerating its regression.

Type: Article
Title: Statins promote the regression of atherosclerosis via activation of the CCR7-dependent emigration pathway in macrophages.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0028534
Publisher version: http://dx.doi.org/10.1371/journal.pone.0028534
Language: English
Additional information: © 2011 Feig et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. These studies were supported by the National Institutes of Health [R01HL084312 and P01HL098055, (EAF, MJG), pre-doctoral fellowship AG029748 (JEF), training grant T32HL098129 (YV)] and grants from Pfizer and Astra-Zeneca (EAF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: Animals, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Apolipoproteins E, Atherosclerosis, Cell Movement, Cholesterol, Disease Progression, Heptanoic Acids, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Macrophages, Mice, Mice, Transgenic, Models, Biological, Monocytes, Promoter Regions, Genetic, Pyrroles, Receptors, CCR7, Response Elements, Sterol Regulatory Element Binding Proteins, Sterols
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1337066
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