Deficiency of ataxia telangiectasia mutated kinase delays inflammatory response in the heart following myocardial infarction.
Deficiency of ataxia telangiectasia mutated kinase delays inflammatory response in the heart following myocardial infarction.
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DOI：
10.1161/jaha.114.001286
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发表时间：
2014-12
影响因子：
5.4
通讯作者：
Singh K
中科院分区：
文献类型：
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作者：
Daniel LL;Daniels CR;Harirforoosh S;Foster CR;Singh M;Singh K
共济失调-毛细血管扩张症是由共济失调毛细血管扩张症突变激酶(ATM)基因突变引起的。我们最近报道，ATM缺乏可减轻心肌梗死(MI)后7天的左心室(LV)功能障碍和扩张，并增加细胞凋亡和纤维化。在这里，我们研究了ATM在急性心肌梗死后心脏炎症反应的诱导和存活信号分子的激活中的作用。检测心肌梗死后1天和3天野生型(WT)和ATM杂合子基因敲除(HKO)小鼠的左心室结构、功能、炎症反应和生化指标。ATM缺乏对心肌梗死面积无影响。心肌梗死引起的心功能下降，以短轴缩短率、射血分数和左心室收缩末期和舒张期容量的变化来衡量，hKO-MI组低于WT-MI组(n=10-12)。心肌梗死后1d，hKO梗死区的中性粒细胞和巨噬细胞数明显低于梗死区。心肌梗死后3d，心肌纤维化程度和肌成纤维细胞标志物α-平滑肌肌动蛋白的表达均高于假手术组，而心肌梗死后3d的WT-β-1活性水平高于假手术组。HKO-Sham组心肌细胞横截面积高于假手术组，两组间差异无统计学意义。两组心肌梗死左室壁内基质金属蛋白酶-9蛋白表达水平相似。在两个时间点，hKO梗死区LV细胞的凋亡率均显著增加。HKO-MI组AKT活性较低，Bax表达较高。ATM缺乏导致扩张性重构减少，延迟急性心肌梗死后的炎症反应。然而，它与肝纤维化和细胞凋亡的增加有关。
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.