title: A wild-type mouse-based model for the regression of inflammation in atherosclerosis.
abstract: Atherosclerosis can be induced by the injection of a gain-of-function mutant of proprotein convertase subtilisin/kexin type 9 (PCSK9)-encoding adeno-associated viral vector (AAVmPCSK9), avoiding the need for knockout mice models, such as low-density lipoprotein receptor deficient mice. As regression of atherosclerosis is a crucial therapeutic goal, we aimed to establish a regression model based on AAVmPCSK9, which will eliminate the need for germ-line genetic modifications. C57BL6/J mice were injected with AAVmPCSK9 and were fed with Western diet for 16 weeks, followed by reversal of hyperlipidemia by a diet switch to chow and treatment with a microsomal triglyceride transfer protein inhibitor (MTPi). Sixteen weeks following AAVmPCSK9 injection, mice had advanced atherosclerotic lesions in the aortic root. Surprisingly, diet switch to chow alone reversed hyperlipidemia to near normal levels, and the addition of MTPi completely normalized hyperlipidemia. A six week reversal of hyperlipidemia, either by diet switch alone or by diet switch and MTPi treatment, was accompanied by regression of atherosclerosis as defined by a significant decrease of macrophages in the atherosclerotic plaques, compared to baseline. Thus, we have established an atherosclerosis regression model that is independent of the genetic background.
authors.affiliation: Department of Medicine, Leon H. Charney Division of Cardiology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Peled
authors.affiliation: Department of Medicine, Leon H. Charney Division of Cardiology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Hitoo
authors.initials: H
authors.lastname: Nishi
authors.affiliation: Department of Medicine, Leon H. Charney Division of Cardiology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Ada
authors.initials: A
authors.lastname: Weinstock
authors.affiliation: Department of Medicine, Leon H. Charney Division of Cardiology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Tessa J
authors.initials: TJ
authors.lastname: Barrett
authors.affiliation: Department of Medicine, Leon H. Charney Division of Cardiology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Felix
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Leon H. Charney Division of Cardiology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Quezada
authors.affiliation: Department of Medicine, Leon H. Charney Division of Cardiology, and the Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000008:administration & dosage; D006937:Hypercholesterolemia / Q000209:etiology; D007249:Inflammation / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout