Deficiency of Ataxia Telangiectasia Mutated Kinase Modulates Cardiac Remodeling Following Myocardial Infarction: Involvement in Fibrosis and Apoptosis

被引:34
|
作者
Foster, Cerrone R. [1 ]
Daniel, Laura L. [1 ]
Daniels, Christopher R. [1 ]
Dalal, Suman [1 ]
Singh, Mahipal [1 ]
Singh, Krishna [1 ]
机构
[1] E Tennessee State Univ, Dept Biomed Sci, James H Quillen Coll Med, James H Quillen Vet Affairs Med Ctr, Johnson City, TN 37614 USA
来源
PLOS ONE | 2013年 / 8卷 / 12期
基金
美国国家卫生研究院;
关键词
MATRIX METALLOPROTEINASES; TISSUE INHIBITORS; MYOCYTE APOPTOSIS; OXIDATIVE STRESS; INFLAMMATORY RESPONSE; ATM; DYSFUNCTION; MICE; PHOSPHORYLATION; P53;
D O I
10.1371/journal.pone.0083513
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 beta-adrenergic receptor stimulation. Here we investigated the role of ATM in cardiac remodeling using myocardial infarction (MI) as a model. Methods and 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 a-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.
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页数:11
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