Nobiletin attenuates adverse cardiac remodeling after acute myocardial infarction in rats via restoring autophagy flux
Nobiletin attenuates adverse cardiac remodeling after acute myocardial infarction in rats via restoring autophagy flux
复制标题
川陈皮素通过恢复自噬通量减轻大鼠急性心肌梗死后不良心脏重塑
DOI：
10.1016/j.bbrc.2017.08.064
复制
发表时间：
2017
影响因子：
3.1
通讯作者：
Liang Zhenye
中科院分区：
文献类型：
--
作者：
Wu Xiaoqian;Zheng Dechong;Qin Yuyan;Liu Zumei;Zhang Guiping;Zhu Xiaoyan;Zeng Lihuan;Liang Zhenye
研究背景我们的前期研究表明，急性心肌梗死（AMI）后，持续性心肌缺血可导致自噬流受损，从而加重心脏重构。在这里，我们研究了Nobiletin，柑橘多甲氧基黄酮，是否可以恢复自噬流量和改善AMI后的心脏预后。结扎大鼠冠状动脉左前降支（LAD）制备AMI模型。诺必列汀能明显改善心肌梗死后心功能不全，减轻心肌重构。同时，Nobiletin对体外培养的H9 C2细胞具有抗氧糖剥夺（OGD）的保护作用。通过检测体内外自噬底物、LC 3B Ⅱ和P62蛋白水平，发现Nobiletin可改善缺血损伤的自噬通量。GFP-mRFP-LC 3腺病毒转染也支持Nobiletin恢复受损的自噬通量。具体而言，自噬通量抑制剂氯喹，但不是3 MA，减轻Nobiletin介导的对OGD的保护。值得注意的是，Nobiletin不影响经典的上游自噬信号通路的激活。然而，Nobiletin增加了溶酶体的酸化，这也支持了Nobiletin加速了自噬通量。综上所述，我们的研究结果表明，Nobiletin恢复了受损的自噬通量，并对急性心肌梗死具有保护作用，表明自噬通量在Nobiletin介导的心肌保护中具有潜在的作用。
BackgroundOur previous study showed that autophagy flux was impaired with sustained heart ischemia, which exacerbated adverse cardiac remodeling after acute myocardial infarction (AMI). Here we investigated whether Nobiletin, a citrus polymethoxylated flavonoids, could restore the autophagy flux and improve cardiac prognosis after AMI. AMI was induced by ligating left anterior descending (LAD) coronary artery in rats. Nobiletin improved the post-infarct cardiac dysfunction significantly and attenuated adverse cardiac remodeling. Meanwhile, Nobiletin protected H9C2 cells against oxygen glucose deprivation (OGD) in vitro. The impaired autophagy flux due to ischemia was ameliorated after Nobiletin treatment by testing the autophagy substrate, LC3BⅡ and P62 protein level both in vivo and in vitro. GFP-mRFP-LC3 adenovirus transfection also supported that Nobiletin restored the impaired autophagy flux. Specifically, the autophagy flux inhibitor, chloroquine, but not 3 MA, alleviated Nobiletin-mediated protection against OGD. Notably, Nobiletin does not affect the activation of classical upstream autophagy signaling pathways. However, Nobiletin increased the lysosome acidation which also supported that Nobiletin accelerated autophagy flux.Taken together, our findings suggested that Nobiletin restored impaired autophagy flux and protected against acute myocardial infarction, suggesting a potential role of autophagy flux in Nobiletin-mediated myocardial protection.