Distinct changes of myocyte autophagy during myocardial hypertrophy and heart failure: association with oxidative stress

Abstract

What is the central question of this study? We investigated the changes of myocyte autophagy during the stages of myocardial hypertrophy and failure and the relationship between autophagy and oxidative stress. What is the main findings and its importance? Myocyte autophagy is reduced during myocardial hypertrophy and increased during heart failure. Reduced autophagy is correlated with myocyte hypertrophy, and increased autophagy is correlated with myocyte apoptosis. The distinct alterations are associated with oxidative stress. Hydrogen peroxide causes distinct, concentration-dependent changes in autophagy in cultured cardiomyocytes. Oxidative stress may mediate the distinct alterations of myocyte autophagy during cardiac hypertrophy and failure. Myocyte autophagy occurs at basal levels in the heart in normal conditions and increases in heart failure. However, the changes of myocyte autophagy during the stages of myocardial hypertrophy and failure are not fully understood. Little is known about the relationship among myocyte autophagy, hypertrophy, apoptosis and oxidative stress. In the present study, we first examined the changes of myocyte autophagy in mice with chronic pressure overload and the relationships between myocyte autophagy and hypertrophy, apoptosis and oxidative stress. Second, we determined the direct role of hydrogen peroxide on autophagy in cultured cardiomyocytes. Eight-week-old male C57BL/6J mice underwent transverse aortic constriction (TAC) or sham operation. In TAC mice, left ventricular wall thickness was increased at 1 week and increased further at 9 weeks. Left ventricular end-diastolic dimension showed no change at 1 week, but increased at 9 weeks in association with systolic dysfunction. Myocyte autophagy was decreased at 1 week after TAC, and the decrease was correlated with increased myocyte size. Myocyte autophagy was increased at 9 weeks after TAC, and the increase was correlated with increased myocyte apoptosis. The alterations in autophagy after TAC were associated with myocardial oxidative stress. Hydrogen peroxide caused distinct, concentration-dependent changes in autophagy in cultured cardiomyocytes. In conclusion, myocyte autophagy was decreased during myocardial hypertrophy and increased during heart failure. The distinct changes were associated with myocyte hypertrophy, apoptosis and oxidative stress. These findings suggest that oxidative stress may mediate the distinct alterations of myocyte autophagy during myocardial hypertrophy and heart failure.