Ataxia telangiectasia mutated kinase (ATM) is involved in cell cycle checkpoints, DNA repair and ... more 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 analyzed 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 Lisoproterenol treatment for 24h. 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 increased ratio of early peak velocity (E wave) to that of the late (A wave) LV filling in KO mice. Basal fibrosis and myocyte cross-sectional area was greater in KO hearts. Expression of fibrosis-related genes (CTGF, PAI-1 and MMP-2) and hypertrophy-related gene (ANP) was higher in KO hearts. β-AR stimulation increased myocyte apoptosis to a similar extent in both groups. Activation of JNKs, and expression and phosphorylation of p53 in response to β-AR stimulation was only observed in WT group. Akt phosphorylation was lower in KO-sham and remained lower following β-AR stimulation in KO group. β-AR stimulation activated GSK-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-ARstimulated apoptosis in WT hearts is associated with p53-and JNKs-dependent mechanism, while decreased Akt activity may play a role in increased myocyte apoptosis in the absence of ATM.
Ataxia telangiectasia mutated kinase (ATM) is involved in cell cycle checkpoints, DNA repair and ... more 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 analyzed 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 Lisoproterenol treatment for 24h. 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 increased ratio of early peak velocity (E wave) to that of the late (A wave) LV filling in KO mice. Basal fibrosis and myocyte cross-sectional area was greater in KO hearts. Expression of fibrosis-related genes (CTGF, PAI-1 and MMP-2) and hypertrophy-related gene (ANP) was higher in KO hearts. β-AR stimulation increased myocyte apoptosis to a similar extent in both groups. Activation of JNKs, and expression and phosphorylation of p53 in response to β-AR stimulation was only observed in WT group. Akt phosphorylation was lower in KO-sham and remained lower following β-AR stimulation in KO group. β-AR stimulation activated GSK-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-ARstimulated apoptosis in WT hearts is associated with p53-and JNKs-dependent mechanism, while decreased Akt activity may play a role in increased myocyte apoptosis in the absence of ATM.
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Papers by Krishna Singh