Abstract 14976: Foxo3a Modulates Mitochondrial and Myocardial Function by Regulating Bnip3 Gene Expression in the Heart
Introduction: FOXO3a is a transcription factor which regulates glucose metabolism, muscle atrophy and cell death in post-mitotic cells. Its role in regulating mitochondrial and myocardial function is not well studied.
Hypothesis: We hypothesized that FOXO3a through BNIP3 modulates mitochondrial function and myocardial energetics, remodeling and function in cardiac stress.
Methods and Results: We utilized a rat model of pressure overload hypertrophy due to ascending aortic banding (AAB) with preserved ejection fraction (EF≊80%), left ventricular (LV) remodeling (LVEDV≥600 μl and LVESV≥120 μl) and diastolic dysfunction as well as studies in adult cardiomyocytes (ACM). Sprague Dawley rats (200 g) underwent AAB. Eight weeks after AAB, rats meeting the above echo criteria, were randomized to receive a tail vein injection of control adeno-associated virus containing GFP without a promoter (AAV9.GNP, n=8) or a dominant-negative FOXO3a mutant (AAV9.dn-FX3a, n=8). At 6 weeks post-injection, echo showed smaller LVESV and higher EF in AAV9.dn-FX3a vs GNP treated rats (p<0.05 for both). LV catheterization showed faster myocardial relaxation, reduced LV diastolic stiffness and enhanced contractility in AAV9.dn-FX3a vs GNP treated rats (p<0.05 for all). Immunoblotting showed lower myocardial expression of the mitochondrial death and mitophagy marker, BNIP3 in AAV9.dn-FX3a vs GNP rats (p<0.05). Ultrastructurally, AAV9.dn-FX3a treated rats had less mitochondrial fragmentation and cristae destruction (p<0.05), more mitochondrial fusion and significant decreases in mitochondrial autophagolysis. Functional assessment of mitochondrial oxidative phosphorylation showed higher expression of electron transport chain complexes I and IV and higher complex IV activity in AAV9.dn-FX3a vs GNP rats (p<0.05 for all). Furthermore, we found that dn-Fx3a as well as BNIP3 knockdown, in vivo and in stressed ACM in vitro, restored the phosphorylation of phospholamban at S16 and the dynamin related protein 1 at S637.
Conclusion: These data suggest that FOXO3a through BNIP3 modulates mitochondrial and myocardial function and plays an important role in myocardial calcium cycling and mitochondrial dynamics in cardiac stress.
Author Disclosures: A.H. Chaanine: None. E. Kohlbrenner: None. S. Gamb: None. A. Guenzel: None. K. Klaus: None. A. Fayyaz: None. S. Nair: None. R.J. Hajjar: None. M.M. Redfield: None.
- © 2016 by American Heart Association, Inc.