MicroRNA-210-mediated proliferation, survival, and angiogenesis promote cardiac repair post myocardial infarction in rodents

被引:97
作者
Arif, Mohammed [1 ]
Pandey, Raghav [1 ]
Alam, Perwez [1 ]
Jiang, Shujia [1 ]
Sadayappan, Sakthivel [2 ]
Paul, Arghya [3 ]
Ahmed, Rafeeq P. H. [1 ]
机构
[1] Univ Cincinnati, Dept Pathol & Lab Med, Coll Med, 231 Albert Sabin Way, Cincinnati, OH 45267 USA
[2] Univ Cincinnati, Coll Med, Dept Internal Med, Cincinnati, OH 45267 USA
[3] Univ Kansas, Sch Engn Chem & Petr Engn, Lawrence, KS 66045 USA
来源
JOURNAL OF MOLECULAR MEDICINE-JMM | 2017年 / 95卷 / 12期
基金
美国国家卫生研究院;
关键词
MiR-210; Cardiomyocyte; Adenomatous polyposis coli; Myocardial infarction; CARDIOMYOCYTE PROLIFERATION; CELL-CYCLE; HYPOXIA; MIR-210; HEART; REGENERATION; EXPRESSION; MICRORNAS; CANCER;
D O I
10.1007/s00109-017-1591-8
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
An innovative approach for cardiac regeneration following injury is to induce endogenous cardiomyocyte (CM) cell cycle re-entry. In the present study, CMs from adult rat hearts were isolated and transfected with cel-miR-67 (control) and rno-miR-210. A significant increase in CM proliferation and mono-nucleation were observed in miR-210 group, in addition to a reduction in CM size, multi-nucleation, and cell death. When compared to control, beta-catenin and Bcl-2 were upregulated while APC (adenomatous polyposis coli), p16, and caspase-3 were downregulated in miR-210 group. In silico analysis predicted cell cycle inhibitor, APC, as a direct target of miR-210 in rodents. Moreover, compared to control, a significant increase in CM survival and proliferation were observed with siRNA-mediated inhibition of APC. Furthermore, miR-210 overexpressing C57BL/6 mice (210-TG) were used for short-term ischemia/reperfusion study, revealing smaller cell size, increased mono-nucleation, decreased multi-nucleation, and increased CM proliferation in 210-TG hearts in contrast to wild-type (NTG). Likewise, myocardial infarction (MI) was created in adult mice, echocardiography was performed, and the hearts were harvested for immunohistochemistry and molecular studies. Compared to NTG, 210-TG hearts showed a significant increase in CM proliferation, reduced apoptosis, upregulated angiogenesis, reduced infarct size, and overall improvement in cardiac function following MI. beta-catenin, Bcl-2, and VEGF (vascular endothelial growth factor) were upregulated while APC, p16, and caspase-3 were downregulated in 210-TG hearts. Overall, constitutive overexpression of miR-210 rescues heart function following cardiac injury in adult mice via promoting CM proliferation, cell survival, and angiogenesis.
引用
收藏
页码:1369 / 1385
页数:17
相关论文
共 44 条
[1]   Cardiac myocyte cell cycle control in development, disease, and regeneration [J].
Ahuja, Preeti ;
Sdek, Patima ;
MacLellan, W. Robb .
PHYSIOLOGICAL REVIEWS, 2007, 87 (02) :521-544
[2]   Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice [J].
Ali, Shah R. ;
Hippenmeyer, Simon ;
Saadat, Lily V. ;
Luo, Liqun ;
Weissman, Irving L. ;
Ardehali, Reza .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2014, 111 (24) :8850-8855
[3]   Use of the mouse aortic ring assay to study angiogenesis [J].
Baker, Marianne ;
Robinson, Stephen D. ;
Lechertier, Tanguy ;
Barber, Paul R. ;
Tavora, Bernardo ;
D'Amico, Gabriela ;
Jones, Dylan T. ;
Vojnovic, Boris ;
Hodivala-Dilke, Kairbaan .
NATURE PROTOCOLS, 2012, 7 (01) :89-104
[4]   Can the cardiomyocyte cell cycle be reprogrammed? [J].
Bicknell, Katrina A. ;
Coxon, Can-Nen H. ;
Brooks, Gavin .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 2007, 42 (04) :706-721
[5]   Cardiovascular regeneration in non-mammalian model systems: What are the differences between newts and man? [J].
Borchardt, Thilo ;
Braun, Thomas .
THROMBOSIS AND HAEMOSTASIS, 2007, 98 (02) :311-318
[6]   MicroRNA microarray expression profiling in human myocardial infarction [J].
Bostjancic, Emanuela ;
Zidar, Nina ;
Glavac, Damjan .
DISEASE MARKERS, 2009, 27 (06) :255-268
[7]   hsa-miR-210 is induced by hypoxia and is an independent prognostic factor in breast cancer [J].
Camps, Carme ;
Buffa, Francesca M. ;
Colella, Stefano ;
Moore, John ;
Sotiriou, Christos ;
Sheldon, Helen ;
Harris, Adrian L. ;
Gleadle, Jonathan M. ;
Ragoussis, Jiannis .
CLINICAL CANCER RESEARCH, 2008, 14 (05) :1340-1348
[8]   mir-17-92 Cluster Is Required for and Sufficient to Induce Cardiomyocyte Proliferation in Postnatal and Adult Hearts [J].
Chen, Jinghai ;
Huang, Zhan-Peng ;
Seok, Hee Young ;
Ding, Jian ;
Kataoka, Masaharu ;
Zhang, Zheng ;
Hu, Xiaoyun ;
Wang, Gang ;
Lin, Zhiqiang ;
Wang, Si ;
Pu, Willam T. ;
Liao, Ronglih ;
Wang, Da-Zhi .
CIRCULATION RESEARCH, 2013, 112 (12) :1557-+
[9]  
Devlin C, 2011, IUBMB LIFE, V63, P94, DOI [10.1002/iub.00427, 10.1002/iub.427]
[10]   Cardiac regeneration: current therapies-future concepts [J].
Doppler, Stefanie A. ;
Deutsch, Marcus-Andre ;
Lange, Ruediger ;
Krane, Markus .
JOURNAL OF THORACIC DISEASE, 2013, 5 (05) :683-697