title: Deficiency of ataxia telangiectasia mutated kinase delays inflammatory response in the heart following myocardial infarction.
abstract: BACKGROUND
  Ataxia‐telangiectasia results from mutations in ataxia telangiectasia mutated kinase (ATM) gene. We recently reported that ATM deficiency attenuates left ventricular (LV) dysfunction and dilatation 7 days after myocardial infarction (MI) with increased apoptosis and fibrosis. Here we investigated the role of ATM in the induction of inflammatory response, and activation of survival signaling molecules in the heart acute post‐MI.
  
  
  RESULTS
  LV structure, function, inflammatory response, and biochemical parameters were measured in wild‐type (WT) and ATM heterozygous knockout (hKO) mice 1 and 3 days post‐MI. ATM deficiency had no effect on infarct size. MI‐induced decline in heart function, as measured by changes in percent fractional shortening, ejection fraction and LV end systolic and diastolic volumes, was lower in hKO‐MI versus WT‐MI (n=10 to 12). The number of neutrophils and macrophages was significantly lower in the infarct LV region of hKO versus WT 1 day post‐MI. Fibrosis and expression of α‐smooth muscle actin (myofibroblast marker) were higher in hKO‐MI, while active TGF‐β1 levels were higher in the WT‐MI 3 days post‐MI. Myocyte cross‐sectional area was higher in hKO‐sham with no difference between the two MI groups. MMP‐9 protein levels were similarly increased in the infarct LV region of both MI groups. Apoptosis was significantly higher in the infarct LV region of hKO at both time points. Akt activation was lower, while Bax expression was higher in hKO‐MI infarct.
  
  
  CONCLUSIONS
  ATM deficiency results in decreased dilative remodeling and delays inflammatory response acute post‐MI. However, it associates with increased fibrosis and apoptosis.
authors.affiliation: Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614
authors.forename: Laura L
authors.initials: LL
authors.lastname: Daniel
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Daniels
authors.forename: Saghar
authors.initials: S
authors.lastname: Harirforoosh
authors.forename: Cerrone R
authors.initials: CR
authors.lastname: Foster
authors.forename: Mahipal
authors.initials: M
authors.lastname: Singh
authors.forename: Krishna
authors.initials: K
authors.lastname: Singh
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006579:Heterozygote; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D009205:Myocarditis / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D020556:Neutrophil Infiltration; D015398:Signal Transduction; D013318:Stroke Volume; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D000199:Actins; D018836:Inflammation Mediators; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse