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.
Keywords: AAV9, adeno-associated virus 9; CMV, cytomegalovirus; CQ, chloroquine; GFP, green red fluorescent protein; HF, heart failure; HF-DB, TAC + MI mice that have undergone debanding; LFEF, left ventricular ejection fraction; LV, left ventricle; MI, myocardial infarction; RFP, red fluorescent protein; TAC, transaortic constriction; TEM, transmission electron microscopic; TFEB, transcription factor EB; autophagy; dsDNA, double stranded DNA; eGFP, enhanced green fluorescent protein; mTOR, mammalian target of rapamycin; reverse left ventricle remodeling.