OxLDL up-regulates microRNA-29b, leading to epigenetic modifications of MMP-2/MMP-9 genes: a novel mechanism for cardiovascular diseases

被引：177
作者：
Chen, Ku-Chung [1 ,6 ]
Wang, Yung-Song [1 ,6 ]
Hu, Ching-Yu [2 ]
Chang, Wei-Chiao [1 ]
Liao, Yi-Chu [2 ,7 ,8 ]
Dai, Chia-Yen [3 ,4 ,5 ]
Juo, Suh-Hang Hank [1 ,6 ]
机构：
[1] Kaohsiung Med Univ, Dept Med Genet, Kaohsiung 807, Taiwan
[2] Kaohsiung Med Univ, Grad Inst Med, Kaohsiung 807, Taiwan
[3] Kaohsiung Med Univ, Fac Internal Med, Coll Med, Kaohsiung 807, Taiwan
[4] Kaohsiung Med Univ, Dept Internal Med, Hepatobiliary Div, Kaohsiung 807, Taiwan
[5] Kaohsiung Med Univ, Dept Occupat & Environm Med, Kaohsiung 807, Taiwan
[6] Kaohsiung Med Univ Hosp, Dept Med Res, Kaohsiung, Taiwan
[7] Taichung Vet Gen Hosp, Neurol Sect, Taichung, Taiwan
[8] Natl Yang Ming Univ, Dept Neurol, Sch Med, Taipei 112, Taiwan
来源：
FASEB JOURNAL | 2011年 / 25卷 / 05期
关键词：
DNA methylation; DNMT3b; atherosclerosis; LOW-DENSITY-LIPOPROTEIN; SMOOTH-MUSCLE-CELLS; MATRIX-METALLOPROTEINASE EXPRESSION; TUMOR-SUPPRESSOR GENES; DNA METHYLTRANSFERASES; OXIDIZED LDL; LUNG-CANCER; IN-VITRO; ATHEROSCLEROSIS; METHYLATION;
D O I：
10.1096/fj.10-174904
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
MicroRNAs (miRNAs), small noncoding RNAs, can control gene expression by binding to their target genes for degradation and/or translational repression. Epigenetic mechanisms are defined as heritable changes in gene expression that do not involve coding sequence modifications. Both mechanisms play an important role in maintaining physiological functions and are also related to disease development. However, few studies report that miRNA-mediated epigenetic regulations are involved in atherosclerosis. In the present study, oxidized low-density lipoprotein (oxLDL) significantly increased primary human aortic smooth muscle cell (HASMC) migration through MMP-2/MMP-9 up-regulation associated with decreased DNA methylation levels. Either mRNA or protein level of DNA methyltransferase 3b (DNMT3b) showed a dose-dependent down-regulation in oxLDL-mediated HASMCs. Knockdown DNMT3b expression enhanced oxLDL-induced DNA demethylation levels of MMP-2/MMP-9. The expression of miRNA-29b (miR-29b), directly targeting DNMT3b, was up-regulated by oxLDL treatment in a dose-dependent manner. OxLDL-mediated MMP-2/MMP-9 up-regulation, DNMT3b down-regulation, and DNA demethylation were all attenuated after knockdown miR-29b expression by antagomiR-29b. We find that oxLDL can up-regulate miR-29b expression, resulting in DNMT3b down-regulation in HASMCs and epigenetically regulated MMP2/MMP-9 genes involved in cell migration. These results show that miRNA-mediated epigenetic regulation may be a novel mechanism in atherosclerosis.-Chen, K.-C., Wang, Y.-S., Hu, C.-Y., Chang, W.-C., Liao, Y C., Dai, C.-Y., Juo, S.-H. H. OxLDL up-regulates microRNA-29b, leading to epigenetic modifications of MMP-2/MMP-9 genes: a novel mechanism for cardiovascular diseases. FASEB J. 25, 1718-1728 (2011). www.fasebj.org
引用
收藏
页码：1718 / 1728
页数：11
相关论文
共 47 条
[1]   Immunolocalization of matrix metalloproteinases in rabbit carotid arteries after balloon denudation [J].
Aoyagi, M ;
Yamamoto, M ;
Azuma, H ;
Nagashima, G ;
Niimi, Y ;
Tamaki, M ;
Hirakawa, K ;
Yamamoto, K .
HISTOCHEMISTRY AND CELL BIOLOGY, 1998, 109 (02) :97-102
[2]   The microRNA.org resource: targets and expression [J].
Betel, Doron ;
Wilson, Manda ;
Gabow, Aaron ;
Marks, Debora S. ;
Sander, Chris .
NUCLEIC ACIDS RESEARCH, 2008, 36 :D149-D153
[3]   MicroRNA-Dependent Regulation of DNA Methyltransferase-1 and Tumor Suppressor Gene Expression by Interleukin-6 in Human Malignant Cholangiocytes [J].
Braconi, Chiara ;
Huang, Nianyuan ;
Patel, Tushar .
HEPATOLOGY, 2010, 51 (03) :881-890
[4]   Epigenetic reactivation of tumor suppressor genes by a novel small-molecule inhibitor of human DNA methyltransferases [J].
Brueckner, B ;
Boy, RG ;
Siedlecki, P ;
Musch, T ;
Kliem, HC ;
Zielenkiewicz, P ;
Suhai, S ;
Wiessler, M ;
Lyko, F .
CANCER RESEARCH, 2005, 65 (14) :6305-6311
[5]   Oxidized LDL affects smooth muscle cell growth through MAPK-mediated actions on nuclear protein import [J].
Chahine, Mirna N. ;
Blackwood, David P. ;
Dibrov, Elena ;
Richard, Melanie N. ;
Pierce, Grant N. .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2009, 46 (03) :431-441
[6]   Claudin-1 Is a Metastasis Suppressor and Correlates with Clinical Outcome in Lung Adenocarcinoma [J].
Chao, Yu-Chih ;
Pan, Szu-Hua ;
Yang, Shuenn-Chen ;
Yu, Sung-Liang ;
Che, Ting-Fang ;
Lin, Chung-Wu ;
Tsai, Mu-Shiun ;
Chang, Gee-Chen ;
Wu, Che-Hsiang ;
Wu, Yi-Ying ;
Lee, Yung-Chie ;
Hong, Tse-Ming ;
Yang, Pan-Chyr .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2009, 179 (02) :123-133
[7]   Sphingosine kinase regulates oxidized low density lipoprotein-mediated calcium oscillations and macrophage survival [J].
Chen, Johnny H. ;
Riazy, Maziar ;
Wang, Shih Wei ;
Dai, Jiazhen Minnie ;
Duronio, Vincent ;
Steinbrecher, Urs P. .
JOURNAL OF LIPID RESEARCH, 2010, 51 (05) :991-998
[8]   Mammalian DNA methyltransferases: A structural perspective [J].
Cheng, Xiaodong ;
Blumenthal, Robert M. .
STRUCTURE, 2008, 16 (03) :341-350
[9]   Epigenetic Control of the Invasion-promoting MT1-MMP/MMP-2/TIMP-2 Axis in Cancer Cells [J].
Chernov, Andrei V. ;
Sounni, Nor Eddine ;
Remacle, Albert G. ;
Strongin, Alex Y. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (19) :12727-12734
[10]   OxLDL induces mitogen-activated protein kinase activation mediated via PI3-kinase/Akt in vascular smooth muscle cells [J].
Chien, MW ;
Chien, CS ;
Hsiao, LD ;
Lin, CH ;
Yang, CM .
JOURNAL OF LIPID RESEARCH, 2003, 44 (09) :1667-1675
12345