Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee.
Center for Inflammation, Infectious Disease, and Immunity, East Tennessee State University, Johnson City, Tennessee.
Am J Physiol Heart Circ Physiol. 2018 Jul 1;315(1):H48-H57. doi: 10.1152/ajpheart.00042.2018. Epub 2018 Apr 13.
Ataxia telangiectasia mutated kinase (ATM) is activated in response to DNA damage. We have previously shown that ATM plays a critical role in myocyte apoptosis and cardiac remodeling after myocardial infarction (MI). Here, we tested the hypothesis that ATM deficiency results in autophagic impairment in the heart early during MI. MI was induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. Structural and biochemical parameters of the heart were measured 4 h after left anterior descending artery ligation. M-mode echocardiography revealed that MI worsens heart function, as evidenced by reduced percent ejection fraction and fractional shortening in both groups. However, MI-induced increase in left ventricular end-diastolic and end-systolic diameters and volumes were significantly lower in hKO hearts. ATM deficiency resulted in autophagic impairment during MI, as evidenced by decreased microtubule-associated protein light chain 3-II increased p62, decreased cathepsin D protein levels, and increased aggresome accumulation. ERK1/2 activation was only observed in WT-MI hearts. Activation of Akt and AMP-activated protein kinase (AMPK) was lower, whereas activation of glycogen synthase kinase (GSK)-3β and mammalian target of rapamycin (mTOR) was higher in hKO-MI hearts. Inhibition of ATM using KU-55933 resulted in autophagic impairment in cardiac fibroblasts, as evidenced by decreased light chain 3-II protein levels and formation of acidic vesicular organelles. This impairment was associated with decreased activation of Akt and AMPK but enhanced activation of GSK-3β and mTOR in KU-55933-treated fibroblasts. Thus, ATM deficiency results in autophagic impairment in the heart during MI and cardiac fibroblasts. This autophagic impairment may occur via the activation of GSK-3β and mTOR and inactivation of Akt and AMPK. NEW & NOTEWORTHY Ataxia telangiectasia mutated kinase (ATM) plays a critical role in myocyte apoptosis and cardiac remodeling after myocardial infarction (MI). Here, we provide evidence that ATM deficiency results in autophagic impairment during MI. Further investigation of the role of ATM in autophagy post-MI may provide novel therapeutic targets for patients with ataxia telangiectasia suffering from heart disease.
共济失调毛细血管扩张突变激酶（ATM）在响应 DNA 损伤时被激活。我们之前已经表明，ATM 在心肌梗死后心肌细胞凋亡和心脏重构中起着关键作用。在这里，我们测试了 ATM 缺陷导致心脏在心肌梗死后早期发生自噬损伤的假设。通过结扎左前降支动脉，在野生型（WT）和 ATM 杂合子敲除（hKO）小鼠中诱导心肌梗死。结扎左前降支动脉后 4 小时测量心脏的结构和生化参数。M 模式超声心动图显示，心肌梗死后心脏功能恶化，两组的射血分数和缩短分数百分比均降低。然而，hKO 心脏中的左心室舒张末期和收缩末期直径和容积的增加幅度明显较低。ATM 缺陷导致心肌梗死后自噬受损，表现为微管相关蛋白轻链 3-II 减少，p62 增加，组织蛋白酶 D 蛋白水平降低，聚集物积累增加。仅在 WT-MI 心脏中观察到 ERK1/2 的激活。hKO-MI 心脏中的 Akt 和 AMP 激活蛋白激酶（AMPK）的激活降低，而糖原合酶激酶（GSK）-3β和哺乳动物雷帕霉素靶蛋白（mTOR）的激活升高。使用 KU-55933 抑制 ATM 导致心肌成纤维细胞自噬受损，表现为轻链 3-II 蛋白水平降低和酸性囊泡细胞器形成。这种损伤与 Akt 和 AMPK 的激活减少但 KU-55933 处理的成纤维细胞中 GSK-3β和 mTOR 的激活增加有关。因此，ATM 缺陷导致心肌梗死后心脏和心肌成纤维细胞中的自噬受损。这种自噬损伤可能是通过 GSK-3β 和 mTOR 的激活以及 Akt 和 AMPK 的失活发生的。新的和值得注意的是，共济失调毛细血管扩张突变激酶（ATM）在心肌梗死后心肌细胞凋亡和心脏重构中起着关键作用。在这里，我们提供了证据表明 ATM 缺陷导致心肌梗死后自噬受损。进一步研究 ATM 在心肌梗死后自噬中的作用可能为患有共济失调毛细血管扩张症并患有心脏病的患者提供新的治疗靶点。
