Abstract 11890: Defining the Role of p62 in Cardiac Hypertrophy and Pathology
Introduction: Accumulation of ubiquitinated proteins and aggregates are increasingly being recognized as playing major roles in cardiac disease and heart failure. Recent work suggests that a protein named p62 plays a regulatory role in the accumulation of ubiquitinated proteins and protein aggregates. Chronic hemodynamic stress causes cardiac hypertrophy and triggers a concomitant increase in p62 and ubiquitinated protein levels.
Hypothesis: p62 expression contributes to proteotoxic accumulation and cardiac hypertrophy.
Methods: An adenovirus was created to drive p62 expression in neonatal cardiomyocytes to study role of p62 in cardiac cell growth and proteotoxic accumulation. Trans-aortic constriction or sham surgeries were performed on wild-type and p62-deficient mice to test if p62 was necessary for pressure-overload induced hypertrophy and pathology.
Results: Overexpression of p62 in cardiomyocytes significantly increased cardiomyocyte size and caused a corresponding increase in aggregate accumulation and cytotoxicity. Wild-type hearts with normal p62 expression developed cardiac hypertrophy, interstitial fibrosis, impaired cardiac function and chamber dilation with eight weeks of pressure-overload. Hearts from mice lacking p62 showed significantly less hypertrophy and fibrosis, better maintenance of cardiac function and were protected against cardiac dilation with hemodynamic stress. Thus the loss of p62 is beneficial against pressure-overload pathology. However the mechanism(s) of p62 action are still being defined. Apoptotic cell death was evaluated by TUNEL staining which showed a significant increase in the percent of apoptotic nuclei in wild-type hearts compared to p62-knockouts following pressure-overload. To test if p62 played a role in regulating protein degradation processes, proteasomal and autophagic function were assayed in cardiomyocytes with and without p62 overexpression. Overexpression of p62 significantly inhibited autophagic flux and increasing p62 expression led to a dose-dependent decrease in proteasome-like activities.
Conclusions: These data show that p62 is an important regulator of proteotoxic pathology and cardiac hypertrophy. Thus targeting p62 may be therapeutically useful.
- © 2012 by American Heart Association, Inc.