Abstract 15965: BAG3 Rescues Contractile Dysfunction Post-MI: Cellular Mechanism
Mutations in BAG3 underlie the development of heart failure with reduced ejection fraction (HFrEF). However, little is known regarding molecular mechanisms of BAG3 in the heart.
Methods: To dissect the role of BAG3 in the heart, mice underwent ligation of the left main coronary artery (MI) or sham surgery. 8 weeks later, MI and Sham mice were randomized to receive either AAV9-GFP (Sham-GFP, MI-GFP) or GFP-tagged-AAV9-BAG3 (MI-BAG3) by intra-orbital injection. Cardiac myocytes were isolated 3 wks later and cellular markers of calcium homeostasis were examined.
Results: MI-GFP mice demonstrated reduced EF and decreased BAG3 (Fig1 A-C) as compared to MI-BAG3 and Sham-GFP mice. Similarly, contraction amplitudes of isolated myocytes were significantly lower in MI-GFP than in Sham-GFP cells, differences were amplified with ISO. Cell shortening and re-lengthening velocities were significantly improved post-MI by AAV9-BAG3. Similarly, systolic [Ca2+]i was significantly lower with ISO in the MI-GFP, but AAV9-BAG3 significantly increased [Ca2+]i transient amplitudes to levels similar to that in sham-GFP (Fig1 D). Since ICa triggers SR Ca2+ and can modulate [Ca2+] transient amplitude we also examined ICa. In the absence of ISO, ICa was not changed in MI-BAG3 as compared with MI-GFP. However, in the presence of ISO, maximal ICa amplitude was significantly lower in MI-GFP than Sham-GFP and AAV9-BAG3 significantly increased maximal ICa amplitudes post-MI. Consistent with early studies from our group, there was a significant increase in the association of the α1c-subunit of Cav1.2 with BAG3 as demonstrated by co-IP studies suggesting that exogenous BAG3 increased complex formation between BAG3 and the L-type Ca2+ channel thereby increasing ICa in the presence of ISO.
Conclusions: Here we show for the first time that rAAV9-BAG3 can restore normal calcium homeostasis in the post-MI heart - suggesting that BAG3 could be a novel therapeutic target for the treatment of post-MI HFrEF.
Author Disclosures: V.D. Myers: None. F. Su: None. T. Knezevic: None. X. Zhang: None. J. Song: None. J. Wang: None. E. Gao: None. J. Rabinowitz: None. M. Muniswamy: None. J.Y. Cheung: None. A.M. Feldman: None.
- © 2016 by American Heart Association, Inc.