Ataxia telangiectasia-mutated kinase deficiency exacerbates left ventricular dysfunction and remodeling late after myocardial infarction

Abstract

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.

Activation of DNA Damage Response and Cellular Senescence in Cardiac Fibroblasts Limit Cardiac Fibrosis After Myocardial Infarction

“…This result is in clear contrast with the report from Daniel et al showing that ATM deficiency exacerbates cardiac dysfunction as well as cardiac fibrosis after MI even at the chronic phase. 29) Given that the mortality rate was higher (44%-61%) in the previous report compared to the present study (˜80%), it is suggested that the difference in the infarct size may explain the discrepancy between the results in both studies.…”

Progressive Liver Disease in Patients With Ataxia Telangiectasia

“…Recently, it was shown that ATM is also involved in metabolic and cardiovascular complications when disrupted (39, 40). In addition, ATM kinase deficiency aggravated left ventricular dysfunction and remodeling late after myocardial infarction in mice (41). Interestingly, mice with ATM haplo-deficiency had decreased vascular endothelial growth factor production and impaired angiogenesis in response to myocardial infarction, leading to accelerated heart failure (41).…”

The Glp-1 Analog Liraglutide Protects Against Angiotensin II and Pressure Overload-Induced Cardiac Hypertrophy via PI3K/Akt1 and AMPKa Signaling

“…As indicated by a large number of researchers, myocardial fibrosis is associated with cardiac hypertrophy, myocardial infarction, hypertension, and heart failure (Daniel et al, 2016; Shimizu and Minamino, 2016; Wu et al, 2016). Myocardial fibrosis is a common pathological change during the development of various heart diseases.…”