Wu Xiaoqian, Zheng Dechong, Qin Yuyan, Liu Zumei, Zhang Guiping, Zhu Xiaoyan, Zeng Lihuan, Liang Zhenye
Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, PR China; Guangzhou Institute of Cardiovascular Disease, Guangzhou Key Laboratory of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, PR China.
Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 511436, PR China.
Biochem Biophys Res Commun. 2017 Oct 14;492(2):262-268. doi: 10.1016/j.bbrc.2017.08.064. Epub 2017 Aug 19.
Our 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.
我们之前的研究表明，持续性心脏缺血会损害自噬通量，这会加剧急性心肌梗死（AMI）后的不良心脏重塑。在此，我们研究了柑橘多甲氧基黄酮诺必亭是否能恢复自噬通量并改善AMI后的心脏预后。通过结扎大鼠左冠状动脉前降支（LAD）诱导AMI。诺必亭显著改善了梗死后的心功能障碍，并减轻了不良心脏重塑。同时，诺必亭在体外保护H9C2细胞免受氧糖剥夺（OGD）。通过检测体内和体外自噬底物LC3BⅡ和P62蛋白水平，发现诺必亭治疗后缺血导致的自噬通量受损得到改善。GFP-mRFP-LC3腺病毒转染也支持诺必亭恢复了受损的自噬通量。具体而言，自噬通量抑制剂氯喹而非3-MA减轻了诺必亭介导的对OGD的保护作用。值得注意的是,诺必亭不影响经典上游自噬信号通路的激活。然而，诺必亭增加了溶酶体酸化，这也支持诺必亭加速了自噬通量。综上所述，我们的研究结果表明，诺必亭恢复了受损的自噬通量并对急性心肌梗死起到保护作用，提示自噬通量在诺必亭介导的心肌保护中具有潜在作用。
