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MicroRNA-33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE(−/−) Mice
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 i...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3540673/ https://www.ncbi.nlm.nih.gov/pubmed/23316322 http://dx.doi.org/10.1161/JAHA.112.003376 |
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author | 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 |
author_facet | 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 |
author_sort | Horie, Takahiro |
collection | PubMed |
description | 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 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. |
format | Online Article Text |
id | pubmed-3540673 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-35406732013-01-11 MicroRNA-33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE(−/−) Mice 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 J Am Heart Assoc Original Research 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 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. Blackwell Publishing Ltd 2012-12-19 /pmc/articles/PMC3540673/ /pubmed/23316322 http://dx.doi.org/10.1161/JAHA.112.003376 Text en © 2012 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell. http://creativecommons.org/licenses/by/2.5/ This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Research 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 MicroRNA-33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE(−/−) Mice |
title | MicroRNA-33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE(−/−) Mice |
title_full | MicroRNA-33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE(−/−) Mice |
title_fullStr | MicroRNA-33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE(−/−) Mice |
title_full_unstemmed | MicroRNA-33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE(−/−) Mice |
title_short | MicroRNA-33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE(−/−) Mice |
title_sort | microrna-33 deficiency reduces the progression of atherosclerotic plaque in apoe(−/−) mice |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3540673/ https://www.ncbi.nlm.nih.gov/pubmed/23316322 http://dx.doi.org/10.1161/JAHA.112.003376 |
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