Targeting the Autophagy-Lysosome Pathway in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure

Visual Abstract

Highlights

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  The biological drivers of reverse LV remodeling are not well understood.

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  Transaortic constriction induced hemodynamic pressure overload superimposed on acute LAD ligation in mice resulted in increased mammalian target of rapamycin activation, decreased autophagic flux, increased mitophagy, decreased mitochondrial oxidative capacity, and accumulation of damaged proteins and organelles in cardiac myocytes

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  Hemodynamic unloading by removing the transaortic constriction leads to reverse LV remodeling, increased mammalian target of rapamycin activation, restoration of autophagic flux, and normalization of mitochondrial oxidative capacity, but incomplete removal of damaged proteins and organelles

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  Enhancing autophagic flux with AAV9- CMV-transcription factor EB in mice that have undergone hemodynamic unloading resulted in more favorable reverse LV remodeling compared with control mice treated with AAV9-CMV-GFP, whereas treating mice that have not undergone hemodynamic unloading with AAV9-CMV-transcription factor EB leads to increased lethality.

Summary

The key biological “drivers” that are responsible for reverse left ventricle (LV) remodeling are not well understood. To gain an understanding of the role of the autophagy-lysosome pathway in reverse LV remodeling, we used a pathophysiologically relevant murine model of reversible heart failure, wherein pressure overload by transaortic constriction superimposed on acute coronary artery (myocardial infarction) ligation leads to a heart failure phenotype that is reversible by hemodynamic unloading. Here we show transaortic constriction + myocardial infarction leads to decreased flux through the autophagy-lysosome pathway with the accumulation of damaged proteins and organelles in cardiac myocytes, whereas hemodynamic unloading is associated with restoration of autophagic flux to normal levels with incomplete removal of damaged proteins and organelles in myocytes and reverse LV remodeling, suggesting that restoration of flux is insufficient to completely restore myocardial proteostasis. Enhancing autophagic flux with adeno-associated virus 9–transcription factor EB resulted in more favorable reverse LV remodeling in mice that had undergone hemodynamic unloading, whereas overexpressing transcription factor EB in mice that have not undergone hemodynamic unloading leads to increased mortality, suggesting that the therapeutic outcomes of enhancing autophagic flux will depend on the conditions in which flux is being studied.