Heavy metal scavenger metallothionein attenuates ER stress-induced myocardial contractile anomalies: role of autophagy.
Heavy metal scavenger metallothionein attenuates ER stress-induced myocardial contractile anomalies: role of autophagy.
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DOI：
10.1016/j.toxlet.2013.12.024
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发表时间：
2014-03-21
影响因子：
3.5
通讯作者：
Ren J
中科院分区：
文献类型：
--
作者：
Yang L;Hu N;Jiang S;Zou Y;Yang J;Xiong L;Ren J
内质网（ER）应激增加了心血管疾病发病率和死亡率的风险，但其潜在机制仍不清楚。本研究旨在研究心肌金属硫蛋白（一种富含半胱氨酸的重金属清除剂）过度表达对ER应激诱导的心肌功能变化的影响及其机制，重点是自噬。对野生型友好病毒B（FVB）和金属硫蛋白转基因小鼠进行ER应激诱导剂衣霉素（1 mg/kg）。我们的研究结果表明，ER应激导致受损的超声心动图和心肌细胞收缩功能，细胞内Ca 2+处理不当。衣霉素促进ER应激和氧化应激，增加左心室收缩末期和舒张末期直径，以及抑制缩短分数和全心脏收缩力，其作用被金属硫蛋白显着减弱或消融。自噬标志物如磷酸化ULK 1、Atg 5、Atg 7、LC 3B和自噬衔接子p62的水平显著上调。这些ER应激诱导的心肌功能、自噬和自噬信号的变化被金属硫蛋白明显减轻或缓解。在体外使用3-甲基腺嘌呤抑制自噬逆转ER应激诱导的心肌细胞收缩缺陷。同时，ER应激诱导的心肌细胞功能障碍被抗氧化剂N-乙酰半胱氨酸减弱。总的来说，这些研究结果表明，金属硫蛋白可能通过减弱心脏自噬来防止ER应激诱导的心脏异常。
Endoplasmic reticulum (ER) stress increases the risk of cardiovascular morbidity and mortality although the underlying mechanism remains elusive. This study was designed to examine the impact of cardiac over-expression of metallothionein, a cysteine-rich heavy metal scavenger, on ER stress-induced changes in myocardial function and underlying mechanism involved with a focus on autophagy. Wild-type friendly virus B (FVB) and metallothionein transgenic mice were subjected to the ER stress inducer tunicamycin (1 mg/kg). Our results showed that ER stress led to compromised echocardiographic and cardiomyocyte contractile function, intracellular Ca2+ mishandling. Tunicamycin promoted ER stress and oxidative stress, increased left ventricular end systolic and diastolic diameter, as well as suppressed fractional shortening and whole heart contractility, the effects of which were significantly attenuated or ablated by metallothionein. Levels of the autophagy markers such as phosphorylated ULK1, Atg5, Atg7, LC3B and the autophagy adaptor p62 were significantly upregulated. These ER stress-induced changes in myocardial function, autophagy and autophagy signaling were distinctly mitigated or alleviated by metallothionein. Inhibition of autophagy using 3-methyladenine in vitro reversed ER stress-induced cardiomyocyte contractile defects. Meanwhile, ER stress-induced cardiomyocyte dysfunction was attenuated by the antioxidant N-acetylcysteine. Collectively, these findings suggested that metallothionein protects against ER stress-induced cardiac anomalies possibly through attenuation of cardiac autophagy.