title: AKT2 Blocks Nucleus Translocation of Apoptosis-Inducing Factor (AIF) and Endonuclease G (EndoG) While Promoting Caspase Activation during Cardiac Ischemia.
abstract: The AKT (protein kinase B, PKB) family has been shown to participate in diverse cellular processes, including apoptosis. Previous studies demonstrated that protein kinase B2 (AKT2-/-) mice heart was sensitized to apoptosis in response to ischemic injury. However, little is known about the mechanism and apoptotic signaling pathway. Here, we show that AKT2 inhibition does not affect the development of cardiomyocytes but increases cell death during cardiomyocyte ischemia. Caspase-dependent apoptosis of both the extrinsic and intrinsic pathway was inactivated in cardiomyocytes with AKT2 inhibition during ischemia, while significant mitochondrial disruption was observed as well as intracytosolic translocation of cytochrome C (Cyto C) together with apoptosis-inducing factor (AIF) and endonuclease G (EndoG), both of which are proven to conduct DNA degradation in a range of cell death stimuli. Therefore, mitochondria-dependent cell death was investigated and the results suggested that AIF and EndoG nucleus translocation causes cardiomyocyte DNA degradation during ischemia when AKT2 is blocked. These data are the first to show a previous unrecognized function and mechanism of AKT2 in regulating cardiomyocyte survival during ischemia by inducing a unique mitochondrial-dependent DNA degradation pathway when it is inhibited.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China. yangshuai923@163.com.
authors.forename: Shuai
authors.initials: S
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China. 14211030585@cpu.edu.cn.
authors.forename: Xinmei
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Center of Translational Medicine and Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China. hxu@diacarta.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China. fancy0703@163.com.
authors.forename: Fan
authors.initials: F
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China. yito-xu@outlook.com.
authors.forename: Yitao
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China. zhelizl@gmail.com.|Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China. zhelizl@gmail.com.|Hubei Key Laboratory of Cardiology, Wuhan 430060, China. zhelizl@gmail.com.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.affiliation: Institut de Recerca Biomèdica de Lleida (IRBLLEIDA)-Universitat de Lleida, Edifici Biomedicina-I. Av. Rovira Roure, 80., 25198 Lleida, Spain. daniel.sanchis@cmb.udl.cat.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sanchis
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China. liangjin1975@cpu.edu.cn.
authors.forename: Liang
authors.initials: L
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China. ybzhang@cpu.edu.cn.
authors.forename: Yubin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210006, China. junmeiye@cpu.edu.cn.
authors.forename: Junmei
authors.initials: J
authors.lastname: Ye
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism; D017202:Myocardial Ischemia / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051033:Apoptosis Inducing Factor; D045304:Cytochromes c; D051057:Proto-Oncogene Proteins c-akt; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D020169:Caspases
keywords: apoptosis; apoptosis-inducing factor (AIF); cardiomyocytes; endonuclease G (EndoG); ischemia; protein kinase B2 (AKT2)