title: Cyclophilin A is an inflammatory mediator that promotes atherosclerosis in apolipoprotein E-deficient mice.
abstract: Cyclophilin A (CyPA; encoded by Ppia) is a ubiquitously expressed protein secreted in response to inflammatory stimuli. CyPA stimulates vascular smooth muscle cell migration and proliferation, endothelial cell adhesion molecule expression, and inflammatory cell chemotaxis. Given these activities, we hypothesized that CyPA would promote atherosclerosis. Apolipoprotein E-deficient (Apoe(-/-)) mice fed a high-cholesterol diet for 16 wk developed more severe atherosclerosis compared with Apoe(-/-)Ppia(-/-) mice. Moreover, CyPA deficiency was associated with decreased low-density lipoprotein uptake, VCAM-1 (vascular cell adhesion molecule 1) expression, apoptosis, and increased eNOS (endothelial nitric oxide synthase) expression. To understand the vascular role of CyPA in atherosclerosis development, bone marrow (BM) cell transplantation was performed. Atherosclerosis was greater in Apoe(-/-) mice compared with Apoe(-/-)Ppia(-/-) mice after reconstitution with CyPA(+/+) BM cells, indicating that vascular-derived CyPA plays a crucial role in the progression of atherosclerosis. These data define a role for CyPA in atherosclerosis and suggest CyPA as a target for cardiovascular therapies.
authors.affiliation: Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Nigro
authors.forename: Kimio
authors.initials: K
authors.lastname: Satoh
authors.forename: Michael R
authors.initials: MR
authors.lastname: O'Dell
authors.forename: Nwe Nwe
authors.initials: NN
authors.lastname: Soe
authors.forename: Zhaoqiang
authors.initials: Z
authors.lastname: Cui
authors.forename: Amy
authors.initials: A
authors.lastname: Mohan
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Abe
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Alexis
authors.forename: Janet D
authors.initials: JD
authors.lastname: Sparks
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Berk
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism*; D050197:Atherosclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D021984:Cyclophilin A / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D021984:Cyclophilin A