JACC. Basic to translational science · 2016
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.
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Knezevic Tijana, Myers Valerie D, Su Feifei, Wang JuFang, Song Jianliang, Zhang Xue-Qian, Gao Erhe, Gao Guofeng, Muniswamy Madesh, Gupta Manish K, Gordon Jennifer, Weiner Kristen N, Rabinowitz Joseph, Ramsey Frederick V, Tilley Douglas G, Khalili Kamel, Cheung Joseph Y, Feldman Arthur M
Аннотация
OBJECTIVES: 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+]i transient amplitudes and increased maximal ICa amplitude.
IMPLICATIONS: The results suggest that BAG3 gene therapy may provide a novel therapeutic option for the treatment of heart failure.
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+]i transient amplitudes and increased maximal ICa amplitude.
IMPLICATIONS: The results suggest that BAG3 gene therapy may provide a novel therapeutic option for the treatment of heart failure.