Lack of Ataxia Telangiectasia Mutated Kinase Induces Structural and Functional Changes in the Heart: Role in β-Adrenergic Receptor-Stimulated Apoptosis
Ataxia telangiectasia mutated kinase (ATM) is involved in cell cycle checkpoints, DNA repair and apoptosis. β-Adrenergic receptor (β-AR) stimulation induces cardiac myocyte apoptosis. Here we analysed basal myocardial structure and function in ATM knockout (KO) mice and tested the hypothesis that ATM modulates β-AR-stimulated myocyte apoptosis. Left ventricular (LV) structure and function, myocyte apoptosis, fibrosis and expression of fibrosis-, hypertrophy- and apoptosis-related proteins were examined in wild-type (WT) and KO mice with or without l-isoprenaline treatment for 24 h. Body and heart weights were lower in KO mice. M-Mode echocardiography showed reduced septal wall thicknesses and LV diameters in KO mice. Doppler echocardiography showed an increased ratio of early peak velocity (E wave) to that of the late LV filling (A wave) in KO mice. Basal fibrosis and myocyte cross-sectional area were greater in KO hearts. Expression of fibrosis-related genes (connective tissue growth factor and plasminogen activator inhibitor-1) and hypertrophy-related gene (atrial natriuretic peptide) was higher in KO hearts. β-Adrenergic receptor stimulation increased myocyte apoptosis to a similar extent in both groups. Activation of c-Jun N-terminal kinases and expression and phosphorylation of p53 in response to β-AR stimulation were only observed in the WT group. Akt phosphorylation was lower in KO sham-treated animals and remained lower following β-AR stimulation in the KO group. β-Adrenergic receptor stimulation activated glycogen synthase kinase-3β to a similar extent in both groups. Thus, lack of ATM induces structural and functional changes in the heart, with enhanced myocardial fibrosis and myocyte hypertrophy. β-Adrenergic receptor-stimulated apoptosis in WT hearts is associated with a p53- and JNKs-dependent mechanism, while decreased Akt activity may play a role in increased myocyte apoptosis in the absence of ATM.
Foster, Cerrone R.; Zha, Qinqin; Daniel, Laura L.; Singh, Mahipal; and Singh, Krishna. 2012. Lack of Ataxia Telangiectasia Mutated Kinase Induces Structural and Functional Changes in the Heart: Role in β-Adrenergic Receptor-Stimulated Apoptosis. Experimental Physiology. Vol.97(4). 506-515. https://doi.org/10.1111/j.1469-445X.2011.01034.x ISSN: 0958-0670