PMID- 29652546 OWN - NLM STAT- MEDLINE DCOM- 20190709 LR - 20240329 IS - 1522-1539 (Electronic) IS - 0363-6135 (Print) IS - 0363-6135 (Linking) VI - 315 IP - 1 DP - 2018 Jul 1 TI - Ataxia telangiectasia mutated kinase deficiency impairs the autophagic response early during myocardial infarction. PG - H48-H57 LID - 10.1152/ajpheart.00042.2018 [doi] AB - 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)-3beta 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-3beta 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-3beta 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. FAU - Thrasher, Patsy R AU - Thrasher PR AD - Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee. FAU - Scofield, Stephanie L C AU - Scofield SLC AD - Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee. FAU - Dalal, Suman AU - Dalal S AUID- ORCID: 0000-0003-4119-6209 AD - Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee. FAU - Crawford, Claire C AU - Crawford CC AD - Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee. FAU - Singh, Mahipal AU - Singh M AD - Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee. FAU - Singh, Krishna AU - Singh K AD - Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee. AD - Center for Inflammation, Infectious Disease, and Immunity, East Tennessee State University, Johnson City, Tennessee. AD - James H. Quillen Veterans Affairs Medical Center, Mountain Home, Tennessee. LA - eng GR - I01 BX000640/BX/BLRD VA/United States GR - I01 BX002332/BX/BLRD VA/United States GR - R15 HL129140/HL/NHLBI NIH HHS/United States GR - C06 RR030651/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20180413 PL - United States TA - Am J Physiol Heart Circ Physiol JT - American journal of physiology. Heart and circulatory physiology JID - 100901228 RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.11.1 (Ataxia Telangiectasia Mutated Proteins) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases) RN - EC 3.4.23.5 (Cathepsin D) SB - IM CIN - Am J Physiol Heart Circ Physiol. 2018 Jul 1;315(1):H80-H82. PMID: 29750568 MH - AMP-Activated Protein Kinase Kinases MH - Animals MH - Ataxia Telangiectasia Mutated Proteins/*deficiency/genetics MH - *Autophagy MH - Cathepsin D/metabolism MH - Cells, Cultured MH - Female MH - Glycogen Synthase Kinase 3 beta/metabolism MH - Male MH - Mice MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Myocardial Infarction/genetics/*metabolism MH - Myocardium/*metabolism/pathology MH - Myofibroblasts/metabolism MH - Protein Kinases/metabolism MH - Rats MH - TOR Serine-Threonine Kinases PMC - PMC6087781 OTO - NOTNLM OT - ataxia telangiectasia mutated kinase OT - autophagy OT - heart OT - myocardial infarction EDAT- 2018/04/14 06:00 MHDA- 2019/07/10 06:00 PMCR- 2019/07/01 CRDT- 2018/04/14 06:00 PHST- 2018/04/14 06:00 [pubmed] PHST- 2019/07/10 06:00 [medline] PHST- 2018/04/14 06:00 [entrez] PHST- 2019/07/01 00:00 [pmc-release] AID - H-00042-2018 [pii] AID - 10.1152/ajpheart.00042.2018 [doi] PST - ppublish SO - Am J Physiol Heart Circ Physiol. 2018 Jul 1;315(1):H48-H57. doi: 10.1152/ajpheart.00042.2018. Epub 2018 Apr 13.