title: Bcl-2-associated athanogene 3 protects the heart from ischemia/reperfusion injury.
abstract: Bcl-2-associated athanogene 3 (BAG3) is an evolutionarily conserved protein expressed at high levels in the heart and the vasculature and in many cancers. While altered BAG3 expression has been associated with cardiac dysfunction, its role in ischemia/reperfusion (I/R) is unknown. To test the hypothesis that BAG3 protects the heart from reperfusion injury, in vivo cardiac function was measured in hearts infected with either recombinant adeno-associated virus serotype 9-expressing (rAAV9-expressing) BAG3 or GFP and subjected to I/R. To elucidate molecular mechanisms by which BAG3 protects against I/R injury, neonatal mouse ventricular cardiomyocytes (NMVCs) in which BAG3 levels were modified by adenovirus expressing (Ad-expressing) BAG3 or siBAG3 were exposed to hypoxia/reoxygenation (H/R). H/R significantly reduced NMVC BAG3 levels, which were associated with enhanced expression of apoptosis markers, decreased expression of autophagy markers, and reduced autophagy flux. The deleterious effects of H/R on apoptosis and autophagy were recapitulated by knockdown of BAG3 with Ad-siBAG3 and were rescued by Ad-BAG3. In vivo, treatment of mice with rAAV9-BAG3 prior to I/R significantly decreased infarct size and improved left ventricular function when compared with mice receiving rAAV9-GFP and improved markers of autophagy and apoptosis. These findings suggest that BAG3 may provide a therapeutic target in patients undergoing reperfusion after myocardial infarction.
authors.affiliation: Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania USA.|Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Su
authors.affiliation: Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania USA.
authors.forename: Valerie D
authors.initials: VD
authors.lastname: Myers
authors.affiliation: Department of Neuroscience.
authors.forename: Tijana
authors.initials: T
authors.lastname: Knezevic
authors.affiliation: Center for Translational Medicine, and.
authors.forename: JuFang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Translational Medicine, and.
authors.forename: Erhe
authors.initials: E
authors.lastname: Gao
authors.affiliation: Center for Translational Medicine, and.
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.affiliation: Department of Neuroscience.
authors.forename: Farzaneh G
authors.initials: FG
authors.lastname: Tahrir
authors.affiliation: Department of Neuroscience.
authors.forename: Manish K
authors.initials: MK
authors.lastname: Gupta
authors.affiliation: Department of Neuroscience.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gordon
authors.affiliation: Center for Translational Medicine, and.
authors.forename: Joseph
authors.initials: J
authors.lastname: Rabinowitz
authors.affiliation: Department of Clinical Sciences, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania USA.
authors.forename: Frederick V
authors.initials: FV
authors.lastname: Ramsey
authors.affiliation: Center for Translational Medicine, and.
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Tilley
authors.affiliation: Department of Neuroscience.
authors.forename: Kamel
authors.initials: K
authors.lastname: Khalili
authors.affiliation: Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania USA.|Center for Translational Medicine, and.
authors.forename: Joseph Y
authors.initials: JY
authors.lastname: Cheung
authors.affiliation: Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania USA.
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Feldman
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001343:Autophagy; D015687:Cell Hypoxia; D002478:Cells, Cultured; D005260:Female; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000473:pathology*; D015427:Reperfusion Injury / Q000517:prevention & control* / Q000628:therapy; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C498806:Bag3 protein, mouse