Adeno-associated Virus Serotype 9 - Driven Expression of BAG3 Improves Left Ventricular Function in Murine Hearts with Left Ventricular Dysfunction Secondary to a Myocardial Infarction.
OBJECTIVE
The present study was undertaken to test the hypothesis that gene delivery of BCL2-Associated Athanogene 3 (BAG3) to the heart of mice with left ventricular dysfunction secondary to a myocardial infarction could enhance cardiac performance.


BACKGROUND
BAG3 is a 575 amino acid protein that has pleotropic functions in the cell including pro-autophagy and anti-apoptosis. Mutations in BAG3 have been associated with both skeletal muscle dysfunction and familial dilated cardiomyopathy and BAG3 levels are diminished in non-familial heart failure.


METHODS
Eight-week-old C57/BL6 mice underwent ligation of the left coronary artery (MI) or sham surgery (Sham). Eight weeks later, mice in both groups were randomly assigned to receive either a retro-orbital injection of rAAV9-BAG3 (MI-BAG3 or Sham-BAG3) or rAAV9-GFP (MI-GFP or Sham GFP). Mice were sacrificed at 3 weeks post-injection and myocytes were isolated from the left ventricle.


RESULTS
MI-BAG3 mice demonstrated a significantly (p < 0.0001) higher left ventricular ejection fraction (LVEF) 9 days after rAAV9-BAG3 injection with further improvement in LVEF, fractional shortening and stroke volume at 3 weeks post-injection without changes in LV mass or LV volume. Injection of rAAV9-BAG3 had no effect on LVEF in Sham mice. The salutary benefits of rAAV9-BAG3 were also observed in myocytes isolated from MI hearts including improved cell shortening (p<0.05), increased systolic [Ca2+]i, increased [Ca2+]itransient amplitudes and increased maximal ICaamplitude.


CONCLUSIONS
The results suggest that BAG3 gene therapy may provide a novel therapeutic option for the treatment of heart failure.
Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennslyvnaia; Department of Neuroscience, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Tijana
T
Knezevic
Department of Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Valerie D
VD
Myers
Department of Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania; Department of Cardiology, TangDu Hospital, Fourth Military Medical University, Xi'an, China.
Feifei
F
Su
Center for Translational Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
JuFang
J
Wang
Center for Translational Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Jianliang
J
Song
Center for Translational Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Xue-Qian
XQ
Zhang
Center for Translational Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Erhe
E
Gao
Department of Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Guofeng
G
Gao
Center for Translational Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Madesh
M
Muniswamy
Department of Neuroscience, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Manish K
MK
Gupta
Department of Neuroscience, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Jennifer
J
Gordon
Department of Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Kristen N
KN
Weiner
Center for Translational Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Joseph
J
Rabinowitz
Department of Biology, College of Science and Technology, Temple University, Philadelphia, Pennslyvnaia.
Frederick V
FV
Ramsey
Center for Translational Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Douglas G
DG
Tilley
Department of Neuroscience, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Kamel
K
Khalili
Department of Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania; Center for Translational Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Joseph Y
JY
Cheung
Department of Medicine, the Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
Arthur M
AM
Feldman