Heavy metal scavenger metallothionein mitigates deep hypothermia-induced myocardial contractile anomalies: role of autophagy (Retracted Article)
Heavy metal scavenger metallothionein mitigates deep hypothermia-induced myocardial contractile anomalies: role of autophagy (Retracted Article)
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DOI：
10.1152/ajpendo.00176.2012
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发表时间：
2013-01-01
影响因子：
5.1
通讯作者：
Ren, Jun
中科院分区：
文献类型：
--
作者：
Jiang, Shasha;Guo, Rui;Ren, Jun
蒋S，郭R，张Y，邹Y，任杰.重金属清除剂金属硫蛋白减轻深缺氧诱导的心肌收缩异常：自噬的作用。Am J Physiol Endocrinol Metab 304：E74-E86，2013.首次发表于2012年11月6日; doi：10.1152/ajpendo.00176.2012.-低温环境暴露可增加心血管疾病的发病率和死亡率，但其潜在机制尚不清楚。本研究旨在研究心脏金属硫蛋白（一种富含半胱氨酸的重金属清除剂）过度表达对低温（4 ℃）诱导的心肌功能变化的影响及其相关机制，重点是自噬。冷暴露（4 ℃，3周）促进氧化应激和蛋白质损伤，增加左心室收缩末期和舒张末期直径，并抑制缩短分数和整个心脏收缩力，其影响显着减弱或消融金属硫蛋白。自噬标志物LC 3B-II、beclin-1和Atg 7的水平在未改变的自噬衔接蛋白p62的情况下显著上调。荧光免疫组织化学显示，低温暴露的小鼠心脏中存在丰富的LC 3B斑点。免疫共沉淀显示Bcl 2和Beclin-1之间的解离增加。冷暴露减少了自噬抑制信号分子Akt和mTOR的磷酸化，增加了ULK 1磷酸化，并抑制了eNOS磷酸化（而其总蛋白表达没有变化）。这些冷应激诱导的心肌功能、自噬和自噬信号级联反应的变化被金属硫蛋白显著缓解或减轻。在体内使用3-甲基腺嘌呤抑制自噬逆转冷缺血诱导的心肌细胞收缩缺陷。抗氧化剂N-乙酰半胱氨酸和溶酶体抑制剂巴弗洛霉素A1可减弱冷应激诱导的心肌细胞功能障碍。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冷应激诱导的心脏异常。
Jiang S, Guo R, Zhang Y, Zou Y, Ren J. Heavy metal scavenger metallothionein mitigates deep hypothermia-induced myocardial contractile anomalies: role of autophagy. Am J Physiol Endocrinol Metab 304: E74-E86, 2013. First published November 6, 2012; doi:10.1152/ajpendo.00176.2012.-Low-ambient temperature environment exposure increased the risk of cardiovascular morbidity and mortality, although the underlying mechanism remains unclear. This study was designed to examine the impact of cardiac overexpression of metallothionein, a cysteine-rich heavy metal scavenger, on low temperature (4 degrees C)-induced changes in myocardial function and the underlying mechanism involved, with a focus on autophagy. Cold exposure (4 degrees C for 3 wk) promoted oxidative stress and protein damage, increased left ventricular end-systolic and -diastolic diameter, and suppressed fractional shortening and whole heart contractility, the effects of which were significantly attenuated or ablated by metallothionein. Levels of the autophagy markers LC3B-II, beclin-1, and Atg7 were significantly upregulated with unchanged autophagy adaptor protein p62. Fluorescent immunohistochemistry revealed abundant LC3B puncta in cold temperature-exposed mouse hearts. Coimmunoprecipitation revealed increased dissociation between Bcl2 and Beclin-1. Cold exposure reduced phosphorylation of the autophagy inhibitory signaling molecules Akt and mTOR, increased ULK1 phosphorylation, and dampened eNOS phosphorylation (without changes in their total protein expression). These cold exposure-induced changes in myocardial function, autophagy, and autophagy signaling cascades were significantly alleviated or mitigated by metallothionein. Inhibition of autophagy using 3-methyladenine in vivo reversed cold exposure-induced cardiomyocyte contractile defects. Cold exposure-induced cardiomyocyte dysfunction was attenuated by the antioxidant N-acetylcysteine and the lysosomal inhibitor bafilomycin A1. Collectively, these findings suggest that metallothionein protects against cold exposure-induced cardiac anomalies possibly through attenuation of cardiac autophagy.