Abstract 13638: AMP-Activated Protein Kinase-Dependent Autophagy in the Transition of Right Ventricular Hypertrophy to Failure
Background: Right ventricular failure (RVF) due to abnormal hemodynamic load is a frequent complication and critical determinant of long-term outcome in many forms of congenital heart disease and pulmonary hypertension. Autophagy is a highly conserved mechanism mediating degradation and recycling of diverse cell/organelle proteins regulated in part by metabolic state via AMP-activated protein kinase (AMPK). The role of autophagy in ventricular dysfunction and RVF are largely unexplored. Here we assessed cardiac autophagy and AMPK activation during development of RVF in infant rabbits subjected to sustained RV pressure overload.
Methods: Newborn rabbits (n = 8/group, 10 d. old) underwent pulmonary artery banding, serial echocardiography, and RV tissue processing for qPCR, qRT-PCR, immunoblot, HPLC, and electron microscopy at 3, 4, and 8 weeks after banding (corresponding to early RVH, established RVH, and early RV failure, respectively).
Results: In compensated (3-4 weeks) RVH, Mito number, density, and Mito DNA (mtDNA) copy number significantly increased; the level of proteins encoded by mtDNA was essentially unchanged. In contrast, onset of RV failure (8 weeks) was accompanied by marked decreases in Mito number, mtDNA copy number, Mito biogenesis and electron transport proteins, and ATP/phosphocreatine. RV autophagic activity significantly increased during the transition from RVH to RVF, as evidenced by markedly increased LC3-II/LC3-I ratio, a highly specific index of autophagic activity, in parallel with phosphorylation/activation of AMPK (increased pAMPK/tAMPK ratio)(Figures).
Conclusion: RV pressure overload induced by pulmonary artery banding leads to RVF and impaired Mito biogenesis. Increased AMPK-dependent autophagy was an early and sustained feature of this process, indicating that load-stimulated dysregulation of autophagic pathways may contribute to impaired Mito biogenesis and the development of RV dysfunction.
- © 2011 by American Heart Association, Inc.