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Deficiency of Ataxia‐telangiectasia Mutated Kinase Induces Autophagic Impairment Following Myocardial Infarction
Author(s) -
Thrasher Patsy R.,
Scofield Stephanie L.C.,
Dalal Suman,
Singh Mahipal,
Singh Krishna
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.846.14
Subject(s) - autophagy , sequestosome 1 , medicine , endocrinology , biology , kinase , ataxia telangiectasia , microbiology and biotechnology , apoptosis , biochemistry , dna damage , dna
Autophagy, a conserved physiological process, is typically triggered by nutritional stress and/or growth factor deprivation and ultimately results in the packaging of cellular components into autophagosomes. These autophagosomes then fuse to lysosomes to be degraded. Although often associated with nutrient deprivation, autophagy is suggested to play a significant role in cardiac remodeling, particularly following myocardial infarction (MI). Ataxia‐telangiectasia mutated kinase (ATM) is a 370 kDa threonine/serine kinase. Mutations in ATM cause a multisystemic disease known as Ataxia‐telangiectasia (AT). Although the role of ATM in cell cycle progression is well known, its role in autophagy is not yet completely understood. The present study tested the hypothesis that deficiency of ATM impairs autophagic response in the heart post‐MI. MI was induced in ~4 month old wild‐type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. The mice were sacrificed 4 hours following MI. Levels of microtubule‐associated protein light chain 3 (LC3), sequestosome 1 (p62), cathepsin D, and phosphorylation of Akt and glycogen synthase kinase 3β (GSK3‐β) were analyzed in the heart lysates using western blots. Ratio of LC3II/LC3I, marker of autophagy induction and autophagosome formation, was significantly lower in hKO‐sham when compared to WT‐sham group (P<0.05 vs WT‐sham; n=7). MI decreased LC3II/LC3I ratio in both groups with no significant difference between the two genotypes. Expression of p62, a marker of autophagic clearance, was significantly higher in hKO‐MI group when compared to hKO‐sham and WT‐MI groups (P<0.05 vs hKO‐sham and WT‐MI; n=6–7). Expression of mature cathepsin D, a lysosomal endopeptidase involved in autophagic clearance, was lower in hKO‐MI group when compared to hKO‐sham. Activation of Akt was lower, while activation of GSK3β was higher in hKO‐MI group when compared to hKO‐sham (P<0.05 vs hKO‐sham; n=6–7). These data suggest that 1) ATM deficiency down‐regulates autophagy in the heart at basal levels; 2) MI down‐regulates autophagy in both genotypes 4 h post‐injury as assessed by the ratio of LCII/LC3I; 3) ATM deficiency impairs autophagic response as indicated by the accumulation of p62 and decreased cathepsin D levels in ATM deficient hearts post‐MI; and 4) autophagic impairment during ATM deficiency involves Akt/GSK3β pathway. Thus, ATM deficiency results in impaired autophagic activity in the heart post‐MI via the involvement of Akt/GSK3β signaling. Support or Funding Information Supported by Department of Veterans Affairs (BX002332), NIH R15HL129140 (NHLBI) and Institutional Research and Improvement account.