title: Statins promote the regression of atherosclerosis via activation of the CCR7-dependent emigration pathway in macrophages.
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.
authors.affiliation: Division of Cardiology (Marc and Ruti Bell Program in Vascular Biology), Department of Medicine, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Feig
authors.forename: Yueting
authors.initials: Y
authors.lastname: Shang
authors.forename: Noemi
authors.initials: N
authors.lastname: Rotllan
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Vengrenyuk
authors.forename: Chaowei
authors.initials: C
authors.lastname: Wu
authors.forename: Raanan
authors.initials: R
authors.lastname: Shamir
authors.forename: Ines Pineda
authors.initials: IP
authors.lastname: Torra
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-Hernando
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis*; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy*; D000069059:Atorvastatin; D002465:Cell Movement / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D018450:Disease Progression; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009000:Monocytes / Q000166:cytology; D011401:Promoter Regions, Genetic; D011758:Pyrroles / Q000494:pharmacology; D054400:Receptors, CCR7 / Q000378:metabolism*; D020218:Response Elements; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism; D013261:Sterols / Q000737:chemistry; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001057:Apolipoproteins E; D000069059:Atorvastatin; D002784:Cholesterol; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D054400:Receptors, CCR7; D051779:Sterol Regulatory Element Binding Proteins; D013261:Sterols; C515370:CCR7 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule