title: Ataxia telangiectasia mutated kinase plays a protective role in β-adrenergic receptor-stimulated cardiac myocyte apoptosis and myocardial remodeling.
abstract: β-Adrenergic receptor (β-AR) stimulation induces cardiac myocyte apoptosis and plays an important role in myocardial remodeling. Here we investigated expression of various apoptosis-related genes affected by β-AR stimulation, and examined first time the role of ataxia telangiectasia mutated kinase (ATM) in cardiac myocyte apoptosis and myocardial remodeling following β-AR stimulation. cDNA array analysis of 96 apoptosis-related genes indicated that β-AR stimulation increases expression of ATM in the heart. In vitro, RT-PCR confirmed increased ATM expression in adult cardiac myocytes in response to β-AR stimulation. Analysis of left ventricular structural and functional remodeling of the heart in wild-type (WT) and ATM heterozygous knockout mice (hKO) 28 days after ISO-infusion showed increased heart weight to body weight ratio in both groups. M-mode echocardiography showed increased percent fractional shortening (%FS) and ejection fraction (EF%) in both groups 28 days post ISO-infusion. Interestingly, the increase in %FS and EF% was significantly lower in the hKO-ISO group. Cardiac fibrosis and myocyte apoptosis were higher in hKO mice at baseline and ISO-infusion increased fibrosis and apoptosis to a greater extent in hKO-ISO hearts. ISO-infusion increased phosphorylation of p53 (Serine-15) and expression of p53 and Bax to a similar extent in both groups. hKO-Sham and hKO-ISO hearts exhibited reduced intact β1 integrin levels. MMP-2 protein levels were significantly higher, while TIMP-2 protein levels were lower in hKO-ISO hearts. MMP-9 protein levels were increased in WT-ISO, not in hKO hearts. In conclusion, ATM plays a protective role in cardiac remodeling in response to β-AR stimulation.
authors.affiliation: Department of Physiology, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, PO Box 70576, Johnson City, TN 37614, USA.
authors.forename: Cerrone R
authors.initials: CR
authors.lastname: Foster
authors.forename: Mahipal
authors.initials: M
authors.lastname: Singh
authors.forename: Venkateswaran
authors.initials: V
authors.lastname: Subramanian
authors.forename: Krishna
authors.initials: K
authors.lastname: Singh
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D020257:Ventricular Remodeling / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019012:Integrin beta1; D011943:Receptors, Adrenergic, beta; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D007545:Isoproterenol