Abstract 15837: Load-Induced Infant Right Ventricular Failure: Dysregulated Mitochondrial Fission-Fusion Program
Background: Right ventricular failure (RVF) due to abnormal hemodynamic load occurs frequently in many forms of congenital heart disease and pulmonary hypertension. We previously reported that mitochondrial (Mt) damage due to increased Mt reactive oxygen species (ROS) was a likely cause of RVF in the abnormally loaded infant RV. Highly regulated dynamic balance of Mt fission/fusion is required to maintain normal Mt morphology and function and to control cell death pathways particularly under stress conditions. Here we assessed 2 key regulators of Mt dynamics, dynamin-related protein 1 (Drp1) and mitofusin 2 (Mfn2), in pressure-overloaded infant RV.
Methods: Newborn rabbits (N=8/group) underwent pulmonary artery banding (or sham surgery) for up to 12 wks; the band was removed in a subgroup after 8 wks. RV function was staged by serial echo and pressure-volume analyses, and expression of Drp1, Mfn2, autophagic activity, Mt ROS, Mt mass and ultrastructure, mtDNA, ATP production, electron transport complex activities and cardiomyocyte apoptosis were quantified.
Results: Elevated Mt ROS occurred 2-3 wks after banding (early RV hypertrophy, RVH) and increased progressively thereafter. Expression of Drp1 increased and Mfn2 decreased significantly beginning at 4 wks; associated abnormalities at 4-6 wks (compensated RVH) included increases in ROS-mediated Mt damage and autophagic activity, decreases in complex I and III activity, and ATP production.
By 8-12 wks (RVF stage), sustained upregulation of Drp1 and marked downregulation of Mfn2 were also associated with markedly increased numbers of ultrastructurally abnormal Mt, increased myocyte apoptosis, and further loss of Mt energetics.
Normalizing RV load by debanding restored Drp1 and Mfn2 and allowed recovery of Mt structure, function, and all other parameters.
Conclusion: The roles of Drp1 and Mfn2 to regulate key aspects of Mt dynamics and cell fate are emerging. Here we found the opposing changes in Drp1 and Mfn2 during the development of infant RVF. Whether the abnormal changes in Drp1 and Mfn2 contributed to this progression by impeding clearance of damaged Mt (via decreased ubiquitinylation) merits further investigation as a potential target to interrupt the transition of RVH to RVF.
- © 2013 by American Heart Association, Inc.