Abstract 596: Cardiac Autophagy is a Maladaptive Response to Hemodynamic Stress
Background: Autophagy is a highly conserved mechanism of protein and organelle degradation linked to several neurodegenerative diseases. Nothing is known about the possible role of autophagy in heart failure.
Methods and Results: Short-term nutrient deprivation, an established trigger of autophagy, induced dramatic increases in the ratio of LC3-II:LC3-I in ventricular lysates, indicative of increased autophagic activity. To determine the specific contribution of cardiomyocyte autophagy, we generated αMHC-GFP-LC3 transgenic mice. Short-term starvation induced a robust increase in the punctate localization of GFP-LC3 in myocytes, demonstrating cardiomyocyte autophagy and confirming the validity of our “autophagy reporter” mice. To test for autophagy in failing heart, we induced pressure overload by severe constriction of the thoracic aorta (sTAB). Fluorescence microscopy demonstrated autophagosome-localized GFP-LC3 in left ventricular myocytes 24h after banding which peaked at 48h and subsequently declined (though remaining elevated relative to control, p<0.05). EM revealed double-membrane autophagosomes in cardiomyocytes in failing heart. Lysosome activity was increased in failing LV as demonstrated by immunostaining for cathepsin D and LAMP-1, suggesting that diminished activity of distal lysosomal pathways was not responsible for autophagosome accumulation. To explore whether cardiomyocyte autophagy is beneficial or maladaptive, we studied mice with targeted disruption of beclin 1, a gene required for autophagosome formation. Heterozygous disruption of beclin 1 led to decreased autophagy in pressure-stressed cardiomyocytes. Heart failure-associated declines in LV systolic function were significantly attenuated in beclin 1 mutants. Beclin 1 over-expressing transgenic mice manifested an amplified pathological response to sTAB. Compared with WT, beclin 1 transgenic mice subjected to standard TAB manifested increased autophagic activity, impaired systolic performance, increased load-induced fibrosis, but similar levels of apoptosis.
Conclusions: These findings implicate autophagy in the pathogenesis of load-induced heart failure and suggest it may be a target for novel therapeutic intervention.