title: MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice.
abstract: BACKGROUND
  Cholesterol efflux from cells to apolipoprotein A-I (apoA-I) acceptors via the ATP-binding cassette transporters ABCA1 and ABCG1 is thought to be central in the antiatherogenic mechanism. MicroRNA (miR)-33 is known to target ABCA1 and ABCG1 in vivo.
  
  
  RESULTS
  We assessed the impact of the genetic loss of miR-33 in a mouse model of atherosclerosis. MiR-33 and apoE double-knockout mice (miR-33(-/-)Apoe(-/-)) showed an increase in circulating HDL-C levels with enhanced cholesterol efflux capacity compared with miR-33(+/+)Apoe(-/-) mice. Peritoneal macrophages from miR-33(-/-)Apoe(-/-) mice showed enhanced cholesterol efflux to apoA-I and HDL-C compared with miR-33(+/+)Apoe(-/-) macrophages. Consistent with these results, miR-33(-/-)Apoe(-/-) mice showed reductions in plaque size and lipid content. To elucidate the roles of miR-33 in blood cells, bone marrow transplantation was performed in these mice. Mice transplanted with miR-33(-/-)Apoe(-/-) bone marrow showed a significant reduction in lipid content in atherosclerotic plaque compared with mice transplanted with miR-33(+/+)Apoe(-/-) bone marrow, without an elevation of HDL-C. Some of the validated targets of miR-33 such as RIP140 (NRIP1) and CROT were upregulated in miR-33(-/-)Apoe(-/-) mice compared with miR-33(+/+)Apoe(-/-) mice, whereas CPT1a and AMPKα were not.
  
  
  CONCLUSIONS
  These data demonstrate that miR-33 deficiency serves to raise HDL-C, increase cholesterol efflux from macrophages via ABCA1 and ABCG1, and prevent the progression of atherosclerosis. Many genes are altered in miR-33-deficient mice, and detailed experiments are required to establish miR-33 targeting therapy in humans.
authors: Department of Cardiovascular Medicine, Kyoto University, Kyoto, Japan.
authors: Takahiro
authors: T
authors: Horie
authors: Osamu
authors: O
authors: Baba
authors: Yasuhide
authors: Y
authors: Kuwabara
authors: Yoshimasa
authors: Y
authors: Chujo
authors: Shin
authors: S
authors: Watanabe
authors: Minako
authors: M
authors: Kinoshita
authors: Masahito
authors: M
authors: Horiguchi
authors: Tomoyuki
authors: T
authors: Nakamura
authors: Kazuhisa
authors: K
authors: Chonabayashi
authors: Masakatsu
authors: M
authors: Hishizawa
authors: Koji
authors: K
authors: Hasegawa
authors: Noriaki
authors: N
authors: Kume
authors: Masayuki
authors: M
authors: Yokode
authors: Toru
authors: T
authors: Kita
authors: Takeshi
authors: T
authors: Kimura
authors: Koh
authors: K
authors: Ono
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology*; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood*; D017931:DNA Primers / Q000737:chemistry; D018450:Disease Progression; D008074:Lipoproteins / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D058226:Plaque, Atherosclerotic / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C577836:ABCA1 protein, human; C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D017931:DNA Primers; D008074:Lipoproteins; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D002784:Cholesterol
keywords: ABCA1; ABCG1; HDL-C; atherosclerosis; microRNA