Document Detail

Ataxia telangiectasia mutated kinase plays a protective role in β-adrenergic receptor-stimulated cardiac myocyte apoptosis and myocardial remodeling.
MedLine Citation:
PMID:  21404020     Owner:  NLM     Status:  MEDLINE    
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.
Cerrone R Foster; Mahipal Singh; Venkateswaran Subramanian; Krishna Singh
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-03-15
Journal Detail:
Title:  Molecular and cellular biochemistry     Volume:  353     ISSN:  1573-4919     ISO Abbreviation:  Mol. Cell. Biochem.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-01     Completed Date:  2011-10-18     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  0364456     Medline TA:  Mol Cell Biochem     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  13-22     Citation Subset:  IM    
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MeSH Terms
Adrenergic beta-Agonists / pharmacology
Antigens, CD29 / genetics,  metabolism
Apoptosis / genetics*
Ataxia Telangiectasia Mutated Proteins
Blotting, Western
Cell Cycle Proteins / genetics*,  metabolism
Cells, Cultured
DNA-Binding Proteins / genetics*,  metabolism
Gene Expression Profiling
Heart / drug effects,  physiopathology
Isoproterenol / pharmacology
Matrix Metalloproteinase 2 / genetics,  metabolism
Matrix Metalloproteinase 9 / genetics,  metabolism
Mice, 129 Strain
Mice, Knockout
Myocardium / metabolism,  pathology
Myocytes, Cardiac / metabolism*
Oligonucleotide Array Sequence Analysis
Phosphorylation / drug effects
Protein-Serine-Threonine Kinases / genetics*,  metabolism
Receptors, Adrenergic, beta / genetics*,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Tumor Suppressor Protein p53 / genetics,  metabolism
Tumor Suppressor Proteins / genetics*,  metabolism
Ventricular Remodeling / genetics
bcl-2-Associated X Protein / genetics,  metabolism
Grant Support
Reg. No./Substance:
0/Adrenergic beta-Agonists; 0/Antigens, CD29; 0/Cell Cycle Proteins; 0/DNA-Binding Proteins; 0/Receptors, Adrenergic, beta; 0/Tumor Suppressor Protein p53; 0/Tumor Suppressor Proteins; 0/bcl-2-Associated X Protein; EC Telangiectasia Mutated Proteins; EC protein, mouse; EC Kinases; EC Metalloproteinase 2; EC Metalloproteinase 9; L628TT009W/Isoproterenol

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