Wang Jia-Pu, Chi Rui-Fang, Wang Ke, Ma Teng, Guo Xiao-Fei, Zhang Xiao-Li, Li Bao, Qin Fu-Zhong, Han Xue-Bin, Fan Bian-Ai
Shanxi Medical University, Taiyuan, Shanxi, 030001, PR China.
The Affiliated Cardiovascular Hospital of Shanxi Medical University, Taiyuan, Shanxi, 030024, PR China.
Exp Physiol. 2018 Apr 1;103(4):461-472. doi: 10.1113/EP086650. Epub 2018 Feb 14.
What is the central question of this study? Does oxidative stress induce impairment of autophagy that results in myocyte hypertrophy early after pressure overload? What is the main finding and its importance? In cultured myocytes, hydrogen peroxide decreased autophagy and increased hypertrophy, and inhibition of autophagy enhanced myocyte hypertrophy. In rats with early myocardial hypertrophy after pressure overload, myocyte autophagy was progressively decreased. The antioxidant N-acetyl-cysteine or the superoxide dismutase mimic tempol prevented the decrease of myocyte autophagy and attenuated myocyte hypertrophy early after pressure overload. These findings suggest that oxidative stress impairs myocyte autophagy that results in myocyte hypertrophy.
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 an impairment of autophagy that results in myocyte hypertrophy. H9C2 cardiomyocytes pretreated with the autophagy inhibitor 3-methyladenine were exposed to 10 and 50 μm hydrogen peroxide (H O ) for 48 h. Male Sprague-Dawley rats underwent abdominal aortic constriction (AAC) or sham operation. The animals were killed 24, 48 or 72 h after surgery. In a separate group, the AAC and sham-operated rats randomly received the antioxidant N-acetyl-cysteine or the superoxide dismutase mimic tempol for 72 h. In H9C2 cardiomyocytes, H O decreased the ratio of microtubule-associated protein light chain 3 (LC3) II to LC3 I and increased P62 and phosphorylated ERK (p-ERK) proteins and myocyte surface area. 3-Methyladenine further increased H O -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 expression of Beclin1, Atg5 and Atg12 was decreased. N-Acetyl-cysteine 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 impairment of autophagy, leading to myocyte hypertrophy. These findings suggest that antioxidants or restoration of autophagy might be of value in the prevention of early myocardial hypertrophy after pressure overload.
本研究的核心问题是什么？氧化应激是否会导致自噬受损，进而在压力超负荷后早期引起心肌细胞肥大？主要发现及其重要性是什么？在培养的心肌细胞中，过氧化氢可降低自噬并增加肥大，而抑制自噬则会增强心肌细胞肥大。在压力超负荷后早期发生心肌肥大的大鼠中，心肌细胞自噬逐渐减少。抗氧化剂N - 乙酰半胱氨酸或超氧化物歧化酶模拟物tempol可预防压力超负荷后早期心肌细胞自噬的减少，并减轻心肌细胞肥大。这些发现表明，氧化应激会损害心肌细胞自噬，进而导致心肌细胞肥大。
心肌细胞自噬不足或过度与左心室（LV）肥大有关。活性氧在体外介导心肌细胞肥大，并在体内介导压力超负荷诱导的LV肥大。在本研究中，我们检验了氧化应激会导致自噬受损进而引起心肌细胞肥大这一假说。用自噬抑制剂3 - 甲基腺嘌呤预处理的H9C2心肌细胞暴露于10和50μm过氧化氢（H₂O₂）中48小时。雄性Sprague - Dawley大鼠接受腹主动脉缩窄（AAC）或假手术。术后24、48或72小时处死动物。在另一组中，AAC大鼠和假手术大鼠随机接受抗氧化剂N - 乙酰半胱氨酸或超氧化物歧化酶模拟物tempol 72小时。在H9C2心肌细胞中，H₂O₂降低了微管相关蛋白轻链3（LC3）II与LC3 I的比例，增加了P62和磷酸化ERK（p - ERK）蛋白以及心肌细胞表面积。3 - 甲基腺嘌呤进一步增加了H₂O₂诱导的p - ERK表达。在AAC术后的大鼠中，心脏与体重之比逐渐增加，LC3 II/I比例逐渐降低，p62和p - ERK表达增加，而Beclin1、Atg5和Atg12的表达降低。N - 乙酰半胱氨酸或tempol可预防AAC大鼠中LC3 II/I比例以及Beclin1和Atg5表达的降低，并减轻LV壁厚度、心肌细胞直径和脑钠肽表达的增加。总之，氧化应激会降低Beclin1和Atg5的表达，导致自噬受损，进而引起心肌细胞肥大。这些发现表明，抗氧化剂或恢复自噬可能对预防压力超负荷后早期心肌肥大具有重要价值。
