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MicroRNA-33 deficiency reduces the progression of atherosclerotic plaque in ApoE-/- mice.

AbstractBACKGROUND:
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.
METHODS AND 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.
AuthorsTakahiro Horie, Osamu Baba, Yasuhide Kuwabara, Yoshimasa Chujo, Shin Watanabe, Minako Kinoshita, Masahito Horiguchi, Tomoyuki Nakamura, Kazuhisa Chonabayashi, Masakatsu Hishizawa, Koji Hasegawa, Noriaki Kume, Masayuki Yokode, Toru Kita, Takeshi Kimura, Koh Ono
JournalJournal of the American Heart Association (J Am Heart Assoc) Vol. 1 Issue 6 Pg. e003376 (Dec 2012) ISSN: 2047-9980 [Electronic] England
PMID23316322 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ABCA1 protein, human
  • ABCG1 protein, mouse
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters
  • Apolipoproteins E
  • Cholesterol, HDL
  • DNA Primers
  • Lipoproteins
  • MicroRNAs
  • Mirn33 microRNA, mouse
  • Cholesterol
Topics
  • ATP Binding Cassette Transporter 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 1
  • ATP-Binding Cassette Transporters (physiology)
  • Animals
  • Apolipoproteins E (physiology)
  • Atherosclerosis (blood, genetics, physiopathology)
  • Blotting, Western
  • Bone Marrow Transplantation
  • Cells, Cultured
  • Cholesterol (metabolism)
  • Cholesterol, HDL (blood)
  • DNA Primers (chemistry)
  • Disease Progression
  • Lipoproteins (physiology)
  • Macrophages, Peritoneal (metabolism)
  • Mice
  • Mice, Knockout
  • MicroRNAs (physiology)
  • Plaque, Atherosclerotic (metabolism, pathology)
  • Real-Time Polymerase Chain Reaction

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