Abstract 17588: Regulation of Cardiac Autophagy by Aldose Reductase
Autophagy is a process that leads to the degradation of dysfunctional cell constituents to maintain cellular homeostasis. Several studies have shown that heart failure is associated with an increase in autophagy, but the mechanisms regulating autophagy in the heart are not well understood. Studies in our laboratory have shown that trans-aortic constriction (TAC) increases myocardial autophagy in mice and that autophagic signaling is enhanced in mice lacking the enzyme aldose reductase (AR). This enzyme catalyzes the reduction of aldehydes such as 4-hydroxy-trans-2-nonenal (HNE) that are generated during lipid peroxidation. However, the role of AR in regulating autophagy is unknown. We hypothesized that pathologic autophagy in the heart is triggered by the accumulation of proteins modified by products of lipid peroxidation and that AR, by removing these products, decreases autophagy. In agreement with this hypothesis, we found close association between HNE-modified proteins and the activation of autophagy (LC3-II conversion) in hearts of mice subjected to TAC. Moreover, perfusion with HNE led to 2-fold increase in LC3-II conversion in adult cardiac myocytes and this increase was significantly greater (3-fold; n=3, P<0.05) in myocytes isolated from AR-null than WT mice. Starvation for 48h led to a 2-fold increase in LC3-II conversion in the heart and this increase was exacerbated in AR-null mice (3-fold; n=3, p<0.05) and diminished (2-fold, n=3, p<0.05) in the hearts of mice with cardio-specific overexpression of AR. Starvation induced AMPK phosphorylation was also increased in AR-null hearts (1.3 to 1.7-fold; n=3, P<0.05). Levels of p62 decreased during starvation in both WT and AR-null hearts. The AR-null hearts were also more susceptible to TAC-induced decrease in fractional shortening and accumulated more HNE-modified proteins (1.5- to 2-fold, n=5, P<0.5) after 2 weeks of TAC than WT hearts. These observations suggest that AR regulates myocardial autophagy by removing protein-modifying products of lipid production.
- © 2012 by American Heart Association, Inc.