α-asarone induces cardiac defects and QT prolongation through mitochondrial apoptosis pathway in zebrafish
α-asarone induces cardiac defects and QT prolongation through mitochondrial apoptosis pathway in zebrafish
复制标题
α-细辛脑通过线粒体凋亡途径诱导斑马鱼心脏缺陷和 QT 延长
DOI：
10.1016/j.toxlet.2020.02.003
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发表时间：
2020-05-15
影响因子：
3.5
通讯作者：
Jin, Meng
中科院分区：
文献类型：
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作者：
Shang, Xueliang;Ji, Xiuna;Jin, Meng
asarone是一种天然的苯丙烯，存在于几种植物中，被广泛用于调味食品和治疗疾病。以往的研究表明-细辛酮具有多种药理功能，但也有报道指出其毒性。然而，人们对它对心血管的影响知之甚少。研究了α细辛酮对斑马鱼的发育毒性，特别是对心脏的毒性。将斑马鱼胚胎暴露于不同浓度的α细辛酮（1、3、5、10和30 μ M）中。发育毒性评估显示，α -细辛酮对死亡率和孵化率没有显著影响。相比之下，斑马鱼的畸形率有浓度依赖性的增加。最具代表性的心脏缺损是心脏畸形率增加、心包水肿面积增大、球静脉窦距离增大、心率降低。值得注意的是，我们发现α细辛酮通过延长平均QTc持续时间和引起t波异常来损害斑马鱼的心功能。心脏发育相关关键转录调控因子tbx5、nkx2.5、hand2和gata5的表达均在α -asarone暴露下发生改变。对其机制的进一步研究表明，α细辛酮主要在斑马鱼心脏区域引发细胞凋亡。此外，处理过的斑马鱼中puma、cyto C、afap1、caspase 3和caspase 9的表达升高表明，线粒体凋亡可能是α -asarone诱导心脏毒性的主要原因。这些发现揭示了细辛酮的心脏发育毒性，扩大了我们对-细辛酮对生物体毒性作用的认识。
alpha-asarone is a natural phenylpropene found in several plants, which are widely used for flavoring foods and treating diseases. Previous studies have demonstrated that alpha-asarone has many pharmacological functions, while some reports indicated its toxicity. However, little is known about its cardiovascular effects. This study investigated developmental toxicity of alpha-asarone in zebrafish, especially the cardiotoxicity. Zebrafish embryos were exposed to different concentrations of alpha-asarone (1, 3, 5, 10, and 30 mu M). Developmental toxicity assessments revealed that alpha-asarone did not markedly affect mortality and hatching rate. In contrast, there was a concentration-dependent increase in malformation rate of zebrafish treated with alpha-asarone. The most representative cardiac defects were increased heart malformation rate, pericardial edema areas, sinus venosusbulbus arteriosus distance, and decreased heart rate. Notably, we found that alpha-asarone impaired the cardiac function of zebrafish by prolonging the mean QTc duration and causing T-wave abnormalities. The expressions of cardiac development-related key transcriptional regulators tbx5, nkx2.5, hand2, and gata5 were all changed under alpha-asarone exposure. Further investigation addressing the mechanism indicated that alpha-asarone triggered apoptosis mainly in the heart region of zebrafish. Moreover, the elevated expression of puma, cyto C, afap1, caspase 3, and caspase 9 in treated zebrafish suggested that mitochondrial apoptosis is likely to be the main reason for alpha-asarone induced cardiotoxicity. These findings revealed the cardiac developmental toxicity of aasarone, expanding our knowledge about the toxic effect of alpha-asarone on living organisms.