Foster Cerrone R, Daniel Laura L, Daniels Christopher R, Dalal Suman, Singh Mahipal, Singh Krishna
Department of Biomedical Sciences, James H Quillen College of Medicine, James H Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, Tennessee, United States of America.
PLoS One. 2013 Dec 16;8(12):e83513. doi: 10.1371/journal.pone.0083513. eCollection 2013.
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 β-adrenergic receptor stimulation. Here we investigated the role of ATM in cardiac remodeling using myocardial infarction (MI) as a model.
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 α-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.
共济失调毛细血管扩张症突变激酶（ATM）是一种在DNA损伤反应中被激活的细胞周期检查点蛋白。我们最近报道，ATM在β-肾上腺素能受体刺激后的心肌重塑中起保护作用。在此，我们以心肌梗死（MI）为模型研究了ATM在心脏重塑中的作用。
在野生型（WT）和ATM杂合敲除（hKO）小鼠MI后7天，检测左心室（LV）结构、功能、凋亡、纤维化以及凋亡和纤维化相关蛋白的水平。两个MI组的梗死面积相似。然而，hKO-MI组的梗死厚度更高。二维M型超声心动图显示，与各自的假手术组相比，两个MI组的短轴缩短率（%FS）和射血分数（EF）百分比均降低。然而，WT-MI组的%FS和EF降低幅度明显大于hKO-MI组。WT-MI组的左心室收缩末期和舒张末期直径大于hKO-MI组。hKO-MI组的纤维化、凋亡和α-平滑肌肌动蛋白染色明显高于WT-MI组。两组梗死区域的MMP-2蛋白水平和活性增加程度相似。WT-MI组非梗死区域的MMP-9蛋白水平高于WT-假手术组。WT组梗死区域的MMP-9蛋白水平和活性明显低于hKO组。两个MI组的TIMP-2蛋白水平同样升高，而hKO组梗死区域的TIMP-4蛋白水平明显降低。hKO组梗死区域的p53蛋白磷酸化水平较高，而锰超氧化物歧化酶的蛋白水平明显低于WT组。在体外，使用KU-55933抑制ATM会增加心肌细胞的氧化应激和凋亡。
