Journal
MOLECULAR AND CELLULAR BIOCHEMISTRY
Volume 353, Issue 1-2, Pages 13-22Publisher
SPRINGER
DOI: 10.1007/s11010-011-0769-6
Keywords
ATM; Apoptosis; Cardiac remodeling; p53; beta 1 Integrin
Categories
Funding
- National Heart, Lung, and Blood Institute [HL-071519, HL-091405, HL-092459]
- Department of Veterans Affairs
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beta-Adrenergic receptor (beta-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 beta-AR stimulation, and examined first time the role of ataxia telangiectasia mutated kinase (ATM) in cardiac myocyte apoptosis and myocardial remodeling following beta-AR stimulation. cDNA array analysis of 96 apoptosis-related genes indicated that beta-AR stimulation increases expression of ATM in the heart. In vitro, RT-PCR confirmed increased ATM expression in adult cardiac myocytes in response to beta-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 beta 1 integrin levels. MMP-2 protein levels were significantly higher, while TIMP-2 protein
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