Abstract 2158: Dysregulation of Mitochondrial Biogenesis Program Triggers Transition of Right Ventricular Hypertrophy to Failure
Background: Right ventricular (RV) failure due to abnormal hemodynamic load is a major problem in congenital heart diseases. We have previously shown that decreased mitochondrial (Mito) electron transport chain (ETC) function occurred in early RV failure. Here we assessed dysregulation of Mito biogenesis program triggers transition of RVH to Failure.
Methods: Newborn rabbits underwent pulmonary artery banding, serial echocardiography, tissue processing for RT-PCR, immunoblot, electron microscopy, and enzyme activity at 3, 4, and 8 weeks (corresponding to early RVH, established RVH, and early RV failure, respectively).
Results: Compensated (3– 4 weeks) RVH demonstrated stable or increased expression of the Nuc coactivators/coregulators of expression of Nuc-encoded Mito genes as well as Mito biogenesis; expression of downstream Nuc- and Mito-encoded genes was also increased, as was Mito number. In contrast, onset of RV failure (8 weeks) was accompanied by reduced expression of Nuc regulatory genes, most Nuc- and Mito-encoded ETC genes (Figures⇓), and Mito number. Interestingly, increased Mito ROS-mediated damage and significantly decreased ETC enzyme activity were already present at 4 weeks.
Conclusion: At the onset of RV failure, expression of the major coregulators of the Nuc and Mito genomes, their target ETC genes, protein subunits, and Mito number were significantly decreased. Increased Complex I-mediated ROS damage preceded those transcriptional and translational abnormalities. This suggests that hypertrophic signaling-induced oxidative stress is early event that causes dysregulation of Mito biogenesis program triggering transition of RVH to Failure.