Abstract 17066: A Metabolic Basis for Histone Acetylation and a Potential Mechanism of Epigenetic Regulation in Right Ventricular Failure
Right ventricular (RV) failure is the most critical determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). There is an increasing awareness of important differences between the left ventricle (LV) and RV. Recently, histone deacetylase (HDAC) inhibitors, which increase histone acetylation, have had promising results on maladaptive LV hypertrophy. However, in RV hypertrophy (RVH), HDAC inhibition resulted in RV failure. Recently, nuclear acetylation processes have been shown to be dependent, in part, on the mitochondria. Since there is evidence of mitochondrial diversity between the RV and LV, we hypothesized that histone acetylation may have a metabolic basis and explain the transition to RV failure. In order to study histone acetylation and its relation to metabolism and disease progression in the failing RV, we used a rat model of monocrotaline (MCT)-induced PAH, in which we studied animals with normal RV function (n=6, RVSP=38±2 mmHg, CO=102±2 ml/min and RV/LV+Septum=22±1), compensated RVH (CRV; n=10, RVSP=66±8 mmHg, CO=80±13 ml/min and RV/LV+Septum=48±3, 2-3 weeks post-MCT) and decompensated RVH (DRV; n=9, RVSP=52±2 mmHg, CO=67±10 ml/min and RV/LV+Septum =58±2, 4-6 weeks post MCT). Compared to control, the myocardium (RV free wall) from CRV animals exhibited decreased mitochondrial activity shown by increased mitochondrial membrane potential and decreased mitochondrial-derived reactive oxygen species (mROS). This was associated with increased RV glucose uptake measured by PET in vivo, suggesting a shift of metabolism away from mitochondria towards glycolysis. CRV animals also showed decreased histone-3 (H3) acetylation (IHC/immunoblot). In contrast, DRV animals showed decreased RV glucose uptake, increased mROS as well as induction of the mitochondrial uncoupling-protein 2 in DRV myocardium. These metabolic/mitochondrial changes were associated with an increase in H3 acetylation in the DRV compared to the CRV animals. We show that metabolism and H3 acetylation closely follow mitochondrial remodeling and that these changes separate CRV from DRV potentially opening a new window in our understanding of RV failure.
- © 2011 by American Heart Association, Inc.