Overexpression of ankyrin repeat domain 1 enhances cardiomyocyte apoptosis by promoting p53 activation and mitochondrial dysfunction in rodents
| Autor: | Jianping Bin, Jingwen Zhang, Xixian Li, Xiaobo Huang, Yulin Liao, Xuan Wei, Ci Chen, Guangjin Luo, Shiping Cao, Guofeng Li, Liang Shen |
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| Rok vydání: | 2015 |
| Předmět: |
ANKRD1
Mitochondrial Diseases Blotting Western Muscle Proteins Apoptosis Blood Pressure Biology Real-Time Polymerase Chain Reaction Mice Animals Gene silencing Myocytes Cardiac Viability assay DNA Primers bcl-2-Associated X Protein Heart Failure Pressure overload Analysis of Variance Gene knockdown Nuclear Proteins General Medicine Molecular biology Angiotensin II Rats Cell biology Mice Inbred C57BL Repressor Proteins Gene Expression Regulation Microscopy Fluorescence Ankyrin repeat Tumor Suppressor Protein p53 |
| Zdroj: | Clinical Science. 128:665-678 |
| ISSN: | 1470-8736 0143-5221 |
| DOI: | 10.1042/cs20140586 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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