Oxidative stress impairs myocyte autophagy, resulting in myocyte hypertrophy

Abstract

Insufficient or excessive myocyte autophagy is associated with left ventricular (LV) hypertrophy. Reactive oxygen species mediate myocyte hypertrophy in vitro and pressure overload-induced LV hypertrophy in vivo. In the present study, we tested the hypothesis that oxidative stress induces autophagy impairment that results in myocyte hypertrophy. H9C2 cardiomyocytes were exposed to 10 and 50 μm hydrogen peroxide (H₂O₂) for 48 h pretreated with autophagy inhibitor 3-methyladenine (3-MA). Male Sprague-Dawley rats underwent abdominal aortic constriction (AAC) or sham operation. The animals were sacrificed at 24, 48 and 72 h after surgery. In a separate group, the AAC and sham-operated rats were randomly received antioxidant N-acetyl-cysteine (NAC) or superoxide dismutase mimic tempol for 72 h. In H9C2 cardiomyocytes, H₂O₂ decreased the LC3 II/I ratio and increased P62 and phosphorylated ERK (p-ERK) proteins and myocyte surface area. 3-MA further increased H₂O₂–induced p-ERK expression. In rats after AAC, the heart to body weight ratio was progressively increased, the LC3 II/I ratio was progressively decreased, p62 and p-ERK expression was increased, and Beclin1, Atg5 and Atg12 expression was decreased. NAC or tempol prevented the decreases in the LC3 II/I ratio and Beclin1 and Atg5 expression and attenuated the increases in LV wall thickness, myocyte diameter and brain natriuretic peptide expression in AAC rats. In conclusion, oxidative stress decreases Beclin1 and Atg5 expression that results in autophagy impairment, leading to myocyte hypertrophy. These findings suggest that antioxidants or restoration of autophagy may be of value in the prevention of early myocardial hypertrophy after pressure overload.

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