The heart of autophagy: deconstructing cardiac proteotoxicity.
The heart is capable of robust structural remodeling, sometimes improving performance and sometimes leading to failure. Recent studies have uncovered a critical role for autophagy in disease-related remodeling of the cardiomyocyte. We have shown previously that hemodynamic load elicits a maladaptive autophagic response in cardiomyocytes which contributes to disease progression. In a recent study, we went on to demonstrate that protein aggregation is a proximal event triggering autophagic clearance mechanisms. The ubiquitin-proteasome-dependent pathways of protein clearance are similarly activated in parallel with processing of stress-induced protein aggregates into aggresomes and clearance through autophagy. These findings in the setting of pressure overload contrast with protein aggregation occurring in a model of protein chaperone malfunction in myocytes, where activation of autophagy is beneficial, antagonizing disease progression. Our findings situate heart disease stemming from environmental stress in the category of proteinopathy and raise important new questions regarding molecular events that elicit adaptive and maladaptive autophagy.
Rothermel
Beverly A
BA
Department of Internal Medicine (Cardiology), University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Hill
Joseph A
JA