MicroRNA‐33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE −/− Mice

Journal of the American Heart Association - Tập 1 Số 6 - 2012
Takahiro Horie1,2, Osamu Baba1, Yasuhide Kuwabara1, Yoshimasa Chujo1, Shin Watanabe1, Minako Kinoshita1, Masahito Horiguchi1, Tomoyuki Nakamura3, Kazuhisa Chonabayashi4, Masakatsu Hishizawa4, Koji Hasegawa5, Noriaki Kume1, Masayuki Yokode2, Toru Kita6, Takeshi Kimura1, Koh Ono1
1Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, 606‐8507, Japan
2Department of Clinical Innovative Medicine, Translational Research Center, Graduate School of Medicine, Kyoto University, Kyoto, 606‐8507, Japan
3Department of Pharmacology, Kansai Medical University, Moriguchi, Osaka, 570‐8506, Japan
4Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 606‐8507, Japan
5Division of Translational Research, Clinical Research Institute, Kyoto Medical Center, Kyoto, 612‐8555, Japan
6Department of Cardiovascular Medicine, Kobe City Medical Center General Hospital, Kobe, 650‐0046, Japan

Tóm tắt

Background Cholesterol efflux from cells to apolipoprotein A‐I (apoA‐I) acceptors via the ATP ‐binding cassette transporters ABCA 1 and ABCG 1 is thought to be central in the antiatherogenic mechanism. Micro RNA (miR)‐33 is known to target ABCA 1 and ABCG 1 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 RIP 140 ( NRIP 1) and CROT were upregulated in miR‐33 −/− Apoe −/− mice compared with miR‐33 +/+ Apoe −/− mice, whereas CPT 1a and AMPK α were not.

Conclusions These data demonstrate that miR‐33 deficiency serves to raise HDL‐C , increase cholesterol efflux from macrophages via ABCA 1 and ABCG 1, 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.

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Journal of the American Heart Association

Tập 1 Số 6

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