Assessment of Autophagy Markers Suggests Increased Activity Following LVAD Therapy

• Published in: JACC. Basic to translational science 2023-09, Vol.8 (9), p.1043-1056
• Main Authors: Martin, Thomas G., Juarros, Miranda A., Cleveland, Joseph C., Bristow, Michael R., Ambardekar, Amrut V., Buttrick, Peter M., Leinwand, Leslie A.
• Format: Article
• Language: English
• Subjects: autolysosome; autophagy; Leading Edge Translational Research; LVAD; reverse remodeling
• ISSN: 2452-302X; 2452-302X
• DOI: 10.1016/j.jacbts.2023.05.015

[Display omitted] •Paired left ventricle samples from 16 patients pre- and post-LVAD display improvements in pathological gene expression signatures post-LVAD.•Gene and protein expression of key autophagy factors increases following mechanical unloading by LVAD.•K63 polyubiquitinated proteins are reduced following LVAD, whereas autolysosome numbers increase, suggesting that a restoration of misfolded protein clearance by autophagy-lysosome pathway is restored with this therapy.•Enzymatic activity of calpains and the 20S proteasome increase post-LVAD and K48 polyubiquitinated proteins decrease, suggesting that proteolysis by these other 2 major protein degradation pathways also increases following mechanical unloading.•These results build on earlier studies indicating the involvement of autophagy in left ventricular reverse remodeling following mechanical unloading by LVAD and lend support for exploring the potential of autophagy-targeting therapies in heart disease. Left ventricular reverse remodeling in heart failure is associated with improved clinical outcomes. However, the molecular features that drive this process are poorly defined. Left ventricular assist devices (LVADs) are the therapy associated with the greatest reverse remodeling and lead to partial myocardial recovery in most patients. In this study, we examined whether autophagy may be implicated in post-LVAD reverse remodeling. We found expression of key autophagy factors increased post-LVAD, while autophagic substrates decreased. Autolysosome numbers increased post-LVAD, further indicating increased autophagy. These findings support the conclusion that mechanical unloading activates autophagy, which may underly the reverse remodeling observed.