MicroRNA-33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE(-/-) Mice

作者：Horie Takahiro; Baba Osamu; Kuwabara Yasuhide; Chujo Yoshimasa; Watanabe Shin; Kinoshita Minako; Horiguchi Masahito; Nakamura Tomoyuki; Chonabayashi Kazuhisa; Hishizawa Masakatsu; Hasegawa Koji; Kume Noriaki; Yokode Masayuki; Kita Toru; Kimura Takeshi; Ono Koh^*

来源：Journal of the American Heart Association, 2012, 1(6).

DOI：10.1161/JAHA.112.003376

• ABCA1
• ABCG1
• atherosclerosis
• HDL-C
• microRNA

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.
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 AMPK alpha 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.

• 出版日期2012-12