title: Deficiency of ataxia telangiectasia mutated kinase modulates cardiac remodeling following myocardial infarction: involvement in fibrosis and apoptosis.
abstract: Ataxia telangiectasia mutated kinase (ATM) is a cell cycle checkpoint protein activated in response to DNA damage. We recently reported that ATM plays a protective role in myocardial remodeling following β-adrenergic receptor stimulation. Here we investigated the role of ATM in cardiac remodeling using myocardial infarction (MI) as a model.
  
  
  RESULTS
  Left ventricular (LV) structure, function, apoptosis, fibrosis, and protein levels of apoptosis- and fibrosis-related proteins were examined in wild-type (WT) and ATM heterozygous knockout (hKO) mice 7 days post-MI. Infarct sizes were similar in both MI groups. However, infarct thickness was higher in hKO-MI group. Two dimensional M-mode echocardiography revealed decreased percent fractional shortening (%FS) and ejection fraction (EF) in both MI groups when compared to their respective sham groups. However, the decrease in %FS and EF was significantly greater in WT-MI vs hKO-MI. LV end systolic and diastolic diameters were greater in WT-MI vs hKO-MI. Fibrosis, apoptosis, and α-smooth muscle actin staining was significantly higher in hKO-MI vs WT-MI. MMP-2 protein levels and activity were increased to a similar extent in the infarct regions of both groups. MMP-9 protein levels were increased in the non-infarct region of WT-MI vs WT-sham. MMP-9 protein levels and activity were significantly lower in the infarct region of WT vs hKO. TIMP-2 protein levels similarly increased in both MI groups, whereas TIMP-4 protein levels were significantly lower in the infarct region of hKO group. Phosphorylation of p53 protein was higher, while protein levels of manganese superoxide dismutase were significantly lower in the infarct region of hKO vs WT. In vitro, inhibition of ATM using KU-55933 increased oxidative stress and apoptosis in cardiac myocytes.
authors.affiliation: Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Cerrone R
authors.initials: CR
authors.lastname: Foster
authors.affiliation: Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Daniel
authors.affiliation: Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Daniels
authors.affiliation: Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Suman
authors.initials: S
authors.lastname: Dalal
authors.affiliation: Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Mahipal
authors.initials: M
authors.lastname: Singh
authors.affiliation: Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, United States of America.
authors.forename: Krishna
authors.initials: K
authors.lastname: Singh
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000235:genetics; D002478:Cells, Cultured; D004452:Echocardiography; D005260:Female; D005355:Fibrosis; D006321:Heart / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D009206:Myocardium / Q000473:pathology; D051381:Rats; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse