Abstract 15079: Sildenafil Promotes Mitochondrial Protein Deacetylation and Improves Mitochondrial Bioenergetics in Single Ventricle Congenital Heart Disease

Introduction: Heart failure (HF) remains the leading cause of death and indication for transplant in single ventricle congenital heart disease (SV). Phosphodiesterase-5 inhibitors (PDE5i) are commonly used for the treatment of SVHF, with the primary target being the pulmonary vasculature. We have previously demonstrated that the failing SV heart is characterized by increased PDE5 activity and impaired mitochondrial function. We hypothesize PDE5i-mediated deacetylation of mitochondrial proteins via activation of sirtuin-3 (SIRT3) promotes enhanced mitochondrial bioenergetics. Methods: Mitochondrial bioenergetics were assessed using an Oroboros O2k high resolution respirometer on freshly explanted permeabilized myocardial tissue from 12 biventricular non-failing controls (BVNF), 21 SVHF, and SVHF hearts treated with PDE5i (n=14) or honokiol (a SIRT3 activator, n=5) for 40 minutes. We examined cardiac lysine acetylation in 8 explanted BVNF and 11 SVHF hearts and mitochondrial lysine acetylation in 2 SVHF samples +/-PDE5i via western blot. Statistical analysis was performed using unpaired Mann-Whitney tests between 2 groups and a Welch ANOVA with post-hoc Dunnett’s T3 multiple comparisons test for 3 group comparisons. Results: Mitochondrial function is impaired in SVHF compared to BVNF, but is rescued by treatment with PDE5i (A) and the SIRT3 activator honokiol (B). SVHF myocardial proteins are hyperacetylated compared to BVNF (representative blot, C, p=0.02). Treatment with PDE5i promotes deacetylation of mitochondrial proteins in failing SV hearts (representative blot, D). Conclusions: Mitochondrial bioenergetics may represent a novel therapeutic target for SVHF. Our data shows that failing SV hearts are typified by impaired mitochondrial function and protein hyperacetylation, and suggests that PDE5i improves mitochondrial function in SVHF through SIRT3 mediated deacetylation of mitochondrial proteins.