The Second Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi, PR China; Shanxi Medical University, Taiyuan 030001, Shanxi, PR China.
Shanxi Medical University, Taiyuan 030001, Shanxi, PR China.
Eur J Pharmacol. 2018 Nov 15;839:47-56. doi: 10.1016/j.ejphar.2018.08.034. Epub 2018 Sep 5.
Increased oxidative stress and myocyte autophagy co-exist in cardiac remodeling. However, it is unclear whether oxidative stress mediates maladaptive myocyte autophagy in pathological ventricular remodeling. In this study, we tested the hypothesis that antioxidants prevent maladaptive myocyte autophagy in pressure overload-induced left ventricular (LV) remodeling. Sprague-Dawley rats underwent abdominal aortic constriction (AAC) or sham operation. The animals were randomized to receive an antioxidant N-acetylcysteine (NAC), an autophagy inhibitor 3-methyladenine (3-MA) or placebo treatment for 2 weeks. We measured LV structure and function by echocardiography and hemodynamics, myocyte autophagy and oxidative stress assessed by 8-hydroxy-2-deoxyguanosine (8-OHdG). AAC rats exhibited increased LV hypertrophy assessed by LV wall thickness and myocyte cross-sectional area. NAC prevented LV hypertrophy in AAC rats. There were no significant differences in LV fractional shortening, end-diastolic dimension and the maximal rate of LV pressure rise among the groups. AAC rats showed an increase in myocardial 8-OHdG that was prevented by NAC. The expression of LC3 II protein, a marker of autophagy, was increased at 2 weeks after AAC. Immunohistochemical scores further confirmed the increase in LC3 expression in AAC rats. The expression of autophagic proteins Beclin1 and Atg12 and ERK activity were also increased in AAC rats. NAC prevented the increases in LC3 II protein, LC3 scores, Beclin1, Atg12 and ERK activity in AAC rats. Inhibition of autophagy by 3-MA prevented LV hypertrophy after pressure overload. These findings suggest that antioxidants may be of value to prevent pressure overload-induced cardiac remodeling through inhibition of maladaptive myocyte autophagy.
氧化应激增加和心肌细胞自噬并存于心脏重构中。然而，氧化应激是否介导病理性心室重构中的适应性不良的心肌细胞自噬尚不清楚。在这项研究中，我们检验了这样一个假设，即抗氧化剂可预防压力超负荷诱导的左心室（LV）重构中的适应性不良的心肌细胞自噬。Sprague-Dawley 大鼠接受腹主动脉缩窄（AAC）或假手术。动物被随机分为接受抗氧化剂 N-乙酰半胱氨酸（NAC）、自噬抑制剂 3-甲基腺嘌呤（3-MA）或安慰剂治疗 2 周。我们通过超声心动图和血流动力学评估 LV 结构和功能，通过 8-羟基-2-脱氧鸟苷（8-OHdG）评估心肌细胞自噬和氧化应激。AAC 大鼠的 LV 壁厚度和心肌细胞横截面积增加，表明 LV 肥厚增加。NAC 预防了 AAC 大鼠的 LV 肥厚。各组之间 LV 短轴缩短分数、舒张末期内径和 LV 压力最大上升率无显著差异。AAC 大鼠心肌 8-OHdG 增加，NAC 可预防。自噬标志物 LC3 II 蛋白的表达在 AAC 后 2 周增加。免疫组化评分进一步证实了 AAC 大鼠 LC3 表达的增加。自噬蛋白 Beclin1 和 Atg12 以及 ERK 活性的表达也在 AAC 大鼠中增加。NAC 可预防 AAC 大鼠 LC3 II 蛋白、LC3 评分、Beclin1、Atg12 和 ERK 活性的增加。自噬抑制 3-MA 可预防压力超负荷后的 LV 肥厚。这些发现表明，抗氧化剂可能通过抑制适应性不良的心肌细胞自噬对预防压力超负荷诱导的心脏重构有价值。
