Ataxia Telangiectasia-Mutated Kinase Deficiency Exacerbates Left Ventricular Dysfunction and Remodeling Late After Myocardial Infarction
Ataxia telangiectasia-mutated kinase (ATM), a cell cycle checkpoint protein, is activated in response to DNA damage and oxidative stress. We have previously shown that ATM deficiency is associated with increased apoptosis and fibrosis and attenuation of cardiac dysfunction early (1–7 days) following myocardial infarction (MI). Here, we tested the hypothesis that enhanced fibrosis and apoptosis, as observed early post-MI during ATM deficiency, exacerbate cardiac dysfunction and remodeling in ATM-deficient mice late post-MI. MIs were induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. Left ventricular (LV) structural and functional parameters were assessed by echocardiography 14 and 28 days post-MI, whereas biochemical parameters were measured 28 days post-MI. hKO-MI mice exhibited exacerbated LV dysfunction as observed by increased LV end-systolic volume and decreased percent fractional shortening and ejection fraction. Infarct size and thickness were not different between the two genotypes. Myocyte cross-sectional area was greater in hKO-MI group. The hKO-MI group exhibited increased fibrosis in the noninfarct and higher expression of α-smooth muscle actin (myofibroblast marker) in the infarct region. Apoptosis and activation of GSK-3β (proapoptotic kinase) were significantly lower in the infarct region of hKO-MI group. Matrix metalloproteinase 2 (MMP-2) expression was not different between the two genotypes. However, MMP-9 expression was significantly lower in the noninfarct region of hKO-MI group. Thus ATM deficiency exacerbates cardiac remodeling late post-MI with effects on cardiac function, fibrosis, apoptosis, and myocyte hypertrophy.
Daniel, Laura L.; Scofield, Stephanie L.; Thrasher, Patsy; Dalal, Suman; Daniels, Christopher R.; Foster, Cerrone R.; Singh, Mahipal; and Singh, Krishna. 2016. Ataxia Telangiectasia-Mutated Kinase Deficiency Exacerbates Left Ventricular Dysfunction and Remodeling Late After Myocardial Infarction. American Journal of Physiology - Heart and Circulatory Physiology. Vol.311(2). H445-H452. https://doi.org/10.1152/ajpheart.00338.2016 ISSN: 0363-6135