title: Loss of apoptosis regulator through modulating IAP expression (ARIA) protects blood vessels from atherosclerosis.
abstract: Atherosclerosis is the primary cause for cardiovascular disease. Here we identified a novel mechanism underlying atherosclerosis, which is provided by ARIA (apoptosis regulator through modulating IAP expression), the transmembrane protein that we recently identified. ARIA is expressed in macrophages present in human atherosclerotic plaque as well as in mouse peritoneal macrophages. When challenged with acetylated LDL, peritoneal macrophages isolated from ARIA-deficient mice showed substantially reduced foam cell formation, whereas the uptake did not differ from that in wild-type macrophages. Mechanistically, loss of ARIA enhanced PI3K/Akt signaling and consequently reduced the expression of acyl coenzyme A:cholesterol acyltransferase-1 (ACAT-1), an enzyme that esterifies cholesterol and promotes its storage, in macrophages. Inhibition of PI3K abolished the reduction in ACAT-1 expression and foam cell formation in ARIA-deficient macrophages. In contrast, overexpression of ARIA reduced Akt activity and enhanced foam cell formation in RAW264.7 macrophages, which was abrogated by treatment with ACAT inhibitor. Of note, genetic deletion of ARIA significantly reduced the atherosclerosis in ApoE-deficient mice. Oil red-O-positive lipid-rich lesion was reduced, which was accompanied by an increase of collagen fiber and decrease of necrotic core lesion in atherosclerotic plaque in ARIA/ApoE double-deficient mice. Analysis of bone marrow chimeric mice revealed that loss of ARIA in bone marrow cells was sufficient to reduce the atherosclerogenesis in ApoE-deficient mice. Together, we identified a unique role of ARIA in the pathogenesis of atherosclerosis at least partly by modulating macrophage foam cell formation. Our results indicate that ARIA could serve as a novel pharmacotherapeutic target for the treatment of atherosclerotic diseases.
authors.affiliation: From the Department of Cardiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566.
authors.forename: Kiyonari
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: From the Department of Cardiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Akakabe
authors.affiliation: From the Department of Cardiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566.
authors.forename: Youhei
authors.initials: Y
authors.lastname: Kitamura
authors.affiliation: From the Department of Cardiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Shimoda
authors.affiliation: From the Department of Cardiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Ono
authors.affiliation: From the Department of Cardiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ueyama
authors.affiliation: From the Department of Cardiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566.
authors.forename: Satoaki
authors.initials: S
authors.lastname: Matoba
authors.affiliation: From the Department of Cardiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii, Kawaramachi-Hirokoji, Kamigyo, Kyoto 602-8566.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamada
authors.affiliation: the Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
authors.forename: Kinta
authors.initials: K
authors.lastname: Hatakeyama
authors.affiliation: the Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1692, Japan.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Asada
authors.affiliation: the Department of Clinical Pharmacy, Kobe Pharmaceutical University, 4-19-1 Motoyama-Kitamachi, Higashinada, Kobe 6588558, and.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Emoto
authors.affiliation: the Department of Clinical Pharmacy, Kobe Pharmaceutical University, 4-19-1 Motoyama-Kitamachi, Higashinada, Kobe 6588558, and ikedak-circ@umin.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D000101:Acetyl-CoA C-Acetyltransferase; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism; D002460:Cell Line; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C094131:NRG1 protein, human; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: ACAT-1; ARIA (Apoptosis Regulator Through Modulating IAP Expression); Akt PKB; Atherosclerosis; Foam Cell Formation; Macrophage; Phosphatidylinositide 3-Kinase (PI3-Kinase); Vascular Biology