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.

• Authors: Laura L Daniel, Stephanie L C Scofield, Patsy Thrasher, Suman Dalal, Christopher R Daniels, Cerrone R Foster, Mahipal Singh, Krishna Singh
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 311 Issue 2 Pg. H445-52 (08 01 2016) ISSN: 1522-1539 [Electronic] United States
• PMID: 27288435 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)

Chemical References

• Actins
• alpha-smooth muscle actin, mouse
• Ataxia Telangiectasia Mutated Proteins
• Atm protein, mouse
• Glycogen Synthase Kinase 3 beta
• Matrix Metalloproteinase 2
• Mmp2 protein, mouse
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Actins (metabolism)
• Animals
• Apoptosis (genetics)
• Ataxia Telangiectasia Mutated Proteins (genetics)
• Blotting, Western
• Cell Size
• Coronary Vessels (surgery)
• Echocardiography
• Female
• Fibrosis
• Glycogen Synthase Kinase 3 beta (metabolism)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Ligation
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Knockout
• Myocardial Infarction (complications)
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (pathology)
• Stroke Volume
• Ventricular Dysfunction, Left (etiology, genetics)
• Ventricular Remodeling (genetics)