Daniel Laura L, Daniels Christopher R, Harirforoosh Saghar, Foster Cerrone R, Singh Mahipal, Singh Krishna
Department of Biomedical Sciences, James H Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614
J Am Heart Assoc. 2014 Dec;3(6):e001286. doi: 10.1161/JAHA.114.001286.
Ataxia‐telangiectasia results from mutations in ataxia telangiectasia mutated kinase (ATM) gene. We recently reported that ATM deficiency attenuates left ventricular (LV) dysfunction and dilatation 7 days after myocardial infarction (MI) with increased apoptosis and fibrosis. Here we investigated the role of ATM in the induction of inflammatory response, and activation of survival signaling molecules in the heart acute post‐MI.
LV structure, function, inflammatory response, and biochemical parameters were measured in wild‐type (WT) and ATM heterozygous knockout (hKO) mice 1 and 3 days post‐MI. ATM deficiency had no effect on infarct size. MI‐induced decline in heart function, as measured by changes in percent fractional shortening, ejection fraction and LV end systolic and diastolic volumes, was lower in hKO‐MI versus WT‐MI (n=10 to 12). The number of neutrophils and macrophages was significantly lower in the infarct LV region of hKO versus WT 1 day post‐MI. Fibrosis and expression of α‐smooth muscle actin (myofibroblast marker) were higher in hKO‐MI, while active TGF‐β1 levels were higher in the WT‐MI 3 days post‐MI. Myocyte cross‐sectional area was higher in hKO‐sham with no difference between the two MI groups. MMP‐9 protein levels were similarly increased in the infarct LV region of both MI groups. Apoptosis was significantly higher in the infarct LV region of hKO at both time points. Akt activation was lower, while Bax expression was higher in hKO‐MI infarct.
ATM deficiency results in decreased dilative remodeling and delays inflammatory response acute post‐MI. However, it associates with increased fibrosis and apoptosis.
共济失调毛细血管扩张症由共济失调毛细血管扩张症突变激酶（ATM）基因突变引起。我们最近报道，心肌梗死（MI）7天后，ATM缺乏可减轻左心室（LV）功能障碍和扩张，同时凋亡和纤维化增加。在此，我们研究了ATM在MI后心脏急性炎症反应诱导及存活信号分子激活中的作用。
在野生型（WT）和ATM杂合敲除（hKO）小鼠MI后1天和3天测量LV结构、功能、炎症反应及生化参数。ATM缺乏对梗死面积无影响。通过左室短轴缩短率、射血分数及LV收缩末期和舒张末期容积变化测量的MI诱导的心脏功能下降，hKO-MI组低于WT-MI组（n = 10至12）。MI后1天，hKO组梗死LV区域的中性粒细胞和巨噬细胞数量显著低于WT组。hKO-MI组纤维化及α-平滑肌肌动蛋白（成肌纤维细胞标志物）表达较高，而MI后3天WT-MI组活性TGF-β1水平较高。hKO-假手术组心肌细胞横截面积较大，两组MI组之间无差异。两组MI组梗死LV区域MMP-9蛋白水平均同样升高。两个时间点hKO组梗死LV区域的凋亡均显著更高。hKO-MI梗死中Akt激活较低，而Bax表达较高。
ATM缺乏导致MI后急性扩张性重塑减少并延迟炎症反应。然而，它与纤维化和凋亡增加有关。
