title: Differential effects of Akt1 signaling on short- versus long-term consequences of myocardial infarction and reperfusion injury.
abstract: A specific role for Akt1 in events following myocardial infarction (MI) and ischemia/reperfusion (I/R) injury is not known. We aimed to determine whether Akt1 deletion in in vivo mouse models of MI and after ischemia I/R injury would alter myocyte survival, cardiac function, and fibrosis. Akt1(+/+) and Akt1(-/-) mice were subjected to MI and I/R, followed by assessment of downstream signaling events and functional consequences. Although no difference in infarct size following short-term MI was observed between Akt1(+/+) and Akt1(-/-) mice, I/R caused substantially more cardiomyocyte apoptosis and tissue damage in Akt1(-/-) mice compared with Akt1(+/+). Importantly, these effects were reversed upon pretreatment with GSK-3 inhibitor SB415286. Counterintuitively, Akt1(-/-) hearts exhibited improved cardiac function following long-term MI compared with Akt1(+/+) and were associated with reduced fibrosis in the left ventricle (LV). Our results demonstrate that Akt1-mediated inhibition of GSK-3 activity is critical for cardioprotection following I/R. However, in the long term, Akt1 contributes to fibrosis in post-MI hearts and might exacerbate cardiac dysfunction showing dichotomous role for Akt1 in cardiac remodeling after MI. Our data suggest that better understanding of the Akt1/GSK-3 pathway may provide insights for better therapeutic strategies in post-MI tissues.
authors.affiliation: 1] Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA [2] Cardiovascular Department, Hainan Provincial People's Hospital, Hainan, China.
authors.forename: Lining
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Bethany A
authors.initials: BA
authors.lastname: Kerr
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Sathyamangla V
authors.initials: SV
authors.lastname: Naga Prasad
authors.affiliation: Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Byzova
authors.affiliation: 1] Clinical and Experimental Therapeutics, University of Georgia and Charlie Norwood VA Medical center, Augusta, GA, USA [2] Department of Medicine, Vascular Biology Center and Cancer Center, Georgia Regents University, Augusta, GA, USA.
authors.forename: Payaningal R
authors.initials: PR
authors.lastname: Somanath
mesh_terms: D000818:Animals; D017209:Apoptosis; D005260:Female; D005355:Fibrosis; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051176:beta Catenin; C514862:Akt1 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3