Abstract 2327: Downregulation of Autophagy Markers in Failing Human Heart with Mechanical Unloading
The failing heart is energy starved. Autophagy is seen in conditions of starvation, ischemia, and heart failure. Activation of autophagy recycles nutrients through the breakdown of damaged organelles and provides new energy substrates. Mechanical unloading with a left ventricular assist device (LVAD) decreases the energy demand of the failing heart. We now tested the hypothesis that LVAD support reverses activation of autophagy. Biopsies of left ventricular myocardium were obtained from 9 patients with idiopathic dilated cardiomyopathy (7 male, 2 female, LVAD support 4 –797 days) at the implantation of the LVAD and upon explant due to heart transplantation or due to death. Transcript levels and protein expression of markers of autophagy were measured by quantitative RT-PCR and Western blotting, respectively. Mechanical unloading significantly decreased transcript levels of Beclin-1 by 30% (p < 0.002), autophagy related gene 5 (Atg-5) by 31% (p < 0.02) and microtubule-associated protein light chain 3 (LC3) by 43% (p < 0.002). Protein levels of Beclin-1 were also significantly reduced by 28% (p < 0.001). Similarly LC3-II which is a specific autophagic marker was reduced after unloading by 26% (p < 0.04) while no change was seen in LC3-I. Gamma-aminobutyric acid receptor-associated protein-like 1 (Gabarapl1), another marker of autophagy showed a reduction of borderline statistical significance (p < 0.1). No significant changes were noted in the expression of Atg-5 (p = 0.17) or sarcoplasmic reticulum Ca2+ ATPase (SERCA2a). Mechanical unloading of the failing human heart decreases markers of autophagy. These findings suggest that LVAD support decreases the need for the cardiomyocyte to break down structural proteins and provides a new mechanism on how the heart rebuilds itself.