The Ankrd1 (ankyrin repeat domain 1) gene is known to be up-regulated in heart failure and acts as a co-activator of p53, modulating its transcriptional activity, but it remains inconclusive whether this gene promotes or inhibits cell apoptosis. In the present study, we attempted to investigate the role of Ankrd1 on AngII (angiotensin II)- or pressure-overload-induced cardiomyocyte apoptosis. In the failing hearts of mice with pressure overload, the protein expression of Ankrd1-encoded CARP (cardiac ankyrin repeat protein) was significantly increased. In NRCs (neonatal rat cardiomyocytes), AngII increased the expression of Ankrd1 and CARP. In the presence of AngII in NRCs, infection with a recombinant adenovirus containing rat Ankrd1 cDNA (Ad-Ankrd1) enhanced the mitochondrial translocation of Bax and phosphorylated p53, increased mitochondrial permeability and cardiomyocyte apoptosis, and reduced cell viability, whereas these effects were antagonized by silencing of Ankrd1. Intra-myocardial injection of Ad-Ankrd1 in mice with TAC (transverse aortic constriction) markedly exacerbated cardiac dysfunction with an increase in the lung weight/body weight ratio and a decrease in left ventricular fractional shortening. Cardiomyocyte apoptosis and the expression of phosphorylated p53 were also significantly increased in Ad-Ankrd1-infected TAC mice, whereas knockdown of Ankrd1 significantly inhibited the apoptotic signal pathway as well as cardiomyocyte apoptosis in pressure-overload mice. These findings indicate that overexpression of Ankrd1 exacerbates pathological cardiac dysfunction through enhancement of cardiomyocyte apoptosis mediated by the up-regulation of p53.
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Research Article|
February 20 2015
Overexpression of ankyrin repeat domain 1 enhances cardiomyocyte apoptosis by promoting p53 activation and mitochondrial dysfunction in rodents
Liang Shen;
Liang Shen
1
*State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Ci Chen;
Ci Chen
1
*State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Xuan Wei;
Xuan Wei
*State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Xixian Li;
Xixian Li
*State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Guangjin Luo;
Guangjin Luo
*State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Jingwen Zhang;
Jingwen Zhang
*State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Jianping Bin;
Jianping Bin
*State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Xiaobo Huang;
Xiaobo Huang
*State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Shiping Cao;
Shiping Cao
*State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Guofeng Li;
Guofeng Li
†Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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Yulin Liao
*State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
Correspondence: Professor Yulin Liao (email [email protected]).
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Publisher: Portland Press Ltd
Received:
September 18 2014
Revision Received:
December 11 2014
Accepted:
December 16 2014
Accepted Manuscript online:
December 16 2014
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2015 Biochemical Society
2015
Clin Sci (Lond) (2015) 128 (10): 665–678.
Article history
Received:
September 18 2014
Revision Received:
December 11 2014
Accepted:
December 16 2014
Accepted Manuscript online:
December 16 2014
Citation
Liang Shen, Ci Chen, Xuan Wei, Xixian Li, Guangjin Luo, Jingwen Zhang, Jianping Bin, Xiaobo Huang, Shiping Cao, Guofeng Li, Yulin Liao; Overexpression of ankyrin repeat domain 1 enhances cardiomyocyte apoptosis by promoting p53 activation and mitochondrial dysfunction in rodents. Clin Sci (Lond) 1 May 2015; 128 (10): 665–678. doi: https://doi.org/10.1042/CS20140586
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