title: Overexpression of ankyrin repeat domain 1 enhances cardiomyocyte apoptosis by promoting p53 activation and mitochondrial dysfunction in rodents.
abstract: 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.
authors.affiliation: *State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Shen
authors.affiliation: *State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Ci
authors.initials: C
authors.lastname: Chen
authors.affiliation: *State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Wei
authors.affiliation: *State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xixian
authors.initials: X
authors.lastname: Li
authors.affiliation: *State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Guangjin
authors.initials: G
authors.lastname: Luo
authors.affiliation: *State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: *State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Bin
authors.affiliation: *State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Huang
authors.affiliation: *State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Shiping
authors.initials: S
authors.lastname: Cao
authors.affiliation: †Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Guofeng
authors.initials: G
authors.lastname: Li
authors.affiliation: *State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001794:Blood Pressure; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D006333:Heart Failure / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D028361:Mitochondrial Diseases / Q000209:etiology / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C104844:Ankrd1 protein, mouse; D017931:DNA Primers; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein