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ATM plays a protective role in β‐adrenergic receptor (β‐AR)‐stimulated cardiac myocyte apoptosis and myocardial remodeling
Author(s) -
Foster Cerrone R.,
Madireddy Sreedhar R.,
Singh Mahipal,
Joyner William L.,
Singh Krishna
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.953.13
Subject(s) - apoptosis , myocyte , medicine , endocrinology , fibrosis , cardiac myocyte , myocardial fibrosis , cardiac function curve , stimulation , biology , cardiac fibrosis , heart failure , biochemistry
β‐AR stimulation induces cardiac myocyte apoptosis and plays an important role in myocardial remodeling. We tested the hypothesis that ATM (ataxia telangiectasia mutated kinase; a protein involved in cell cycle checkpoints, DNA repair and apoptosis) plays a protective role in myocyte apoptosis and myocardial remodeling following β‐AR stimulation. Left ventricular structure and function, myocyte apoptosis, and fibrosis were examined in wild‐type (WT) and ATM heterozygous knockout mice (hKO) 28 days after L‐isoproterenol (ISO; 400µg/kg/h) infusion. Heart weight to body weight ratio was higher in hKO group with or without ISO‐infusion. Echocardiographic parameters were not different between the two sham groups. ISO‐infusion increased percent fractional shortening (%FS) and ejection fraction (EF) in both groups. Interestingly, the increase in %FS and EF was lower in hKO‐ISO group (p<0.01). Myocyte apoptosis and fibrosis were higher in hKO‐sham vs WT‐sham. ISO‐infusion increased apoptosis and fibrosis in both groups. However, the increase in fibrosis and apoptosis was higher in hKO‐ISO (p<0.01).Western blot analysis revealed increased p53 and reduced MMP‐9 protein levels in hKO‐ISO. Thus, deficiency of ATM induces remodeling at basal levels. Chronic β‐AR stimulation adversely affects heart function in ATM deficient mice with increased myocyte apoptosis and myocardial fibrosis.