Asiatic acid alleviates ischemic myocardial injury in mice by modulating mitophagy- and glycophagy-based energy metabolism
Asiatic acid alleviates ischemic myocardial injury in mice by modulating mitophagy- and glycophagy-based energy metabolism
复制标题
积雪草酸通过调节线粒体自噬和糖自噬能量代谢减轻小鼠缺血性心肌损伤
DOI：
10.1038/s41401-021-00763-9
复制
发表时间：
2021-09
影响因子：
8.2
通讯作者：
Ling Gao
中科院分区：
文献类型：
--
作者：
Fan Qiu;Yi Yuan;Wei Luo;Yanshan Gong;Zhongming Zhang;Zhongmin Liu;Ling Gao
心肌梗死（MI）会导致心肌能量代谢紊乱，最终导致预后不良。（糖噬）和线粒体自噬积雪草酸（Asiatic acid，AA）是一种从传统中药积雪草（Centella asiatica）中提取的五环三萜类化合物，具有抗炎、抗氧化、和抗凋亡活性。AA已被发现通过逆转线粒体功能障碍来减轻局灶性脑和肝缺血损伤。在这项研究中，本研究探讨了AA是否通过激活糖噬和线粒体自噬来改善能量平衡，从而发挥心肌保护作用。用AA（2-50 μM）处理显著增加了细胞活力，并通过增加的ATP水平和磷酸肌酸/ATP比率证明了改善了能量代谢。在MI小鼠模型中研究了体内心脏保护作用。（5-125 mg·kg~（-1）·d~（-1）IG）可明显减少心肌梗死面积和缺血心肌损伤，AA治疗还促进了线粒体自噬，减轻了线粒体水肿，这一点在体内缺血心肌中的线粒体自噬体数量增加和线粒体自噬增加中得到了证明。在体外ODG处理的心肌细胞中，轻链3（LC 3）-II共定位。线粒体自噬激活伴随着AMPK信号通路的激活。AMPK的敲低消除了AA激活的线粒体自噬。此外，我们发现糖噬在OGD心肌细胞中上调，这通过增加淀粉结合域蛋白1（STBD 1）-GABA A型受体相关蛋白样蛋白1结果表明，AA处理后，GABARAPL 1和GABARAPL 1的相互作用和细胞外酸化率均显著降低，而AA处理后，GABARAPL 1和GABARAPL 1的相互作用和细胞外酸化率均显著降低，而AA处理后，GABARAPL 1和GABARAPL 1的相互作用和细胞外酸化率均显著降低。这些结果表明AA通过PI 3 K/Akt和AMPK途径调节以糖噬和线粒体自噬为基础的能量代谢，从而保护缺血心肌细胞。
Myocardial infarction (MI) causes disturbances in myocardial energy metabolism,ultimately leading to a poor prognosis.Cytosolic glycogen autophagy (glycophagy) and mitochondrial autophagy (mitophagy) are upregulated in MI to optimize energy metabolism but to a limited extent.Asiatic acid (AA),a pentacyclic triterpene derived from the traditional Chinese herb Centella asiatica,displays anti-inflammatory,antioxidant,and antiapoptotic activities.AA has been found to alleviate focal cerebral and liver ischemic injury by reversing mitochondrial dysfunction.In this study,we investigated whether AA exerted cardioprotective effects against MI by activating glycophagy and mitophagy to improve the energy balance.In vitro cardioprotective effects were examined in neonatal mouse cardiomyocytes subjected to oxygen-glucose deprivation for 12 h.Treatment with AA (2-50 µM) significantly increased cell viability and improved the energy metabolism evidenced by increased ATP level and phosphocreatine/ATP ratio.In vivo cardioprotective effects were studied in a mouse model of MI.Administration of AA (5-125 mg·kg~(-1)·d~(-1) ig) significantly reduced infarct size and ischemic myocardial injury,and improved cardiac function.AA treatment also promoted mitophagy and relieved mitochondrial edema evidenced by increased number of mitophagosomes in ischemic myocardium in vivo and increased mitochondria-light chain 3 (LC3)-II colocalization in ODG-treated cardiomyocytes in vitro.Mitophagy activation was accompanied by activation of the AMPK signaling pathway.Knockdown of AMPK abolished AA-activated mitophagy.Furthermore,we showed that glycophagy was upregulated in OGD cardiomyocytes evidenced by increased starch binding domain protein 1 (STBD1)-GABA type A receptor-associated protein-like 1 (GABARAPL1) interaction and extracellular acidification rate,whereas AA treatment furtherpromoted glycophagy accompanied by PI3K/Akt activation.PI3K inhibitor LY294002 or Akt inhibitor GSK690693 blocked the effects of AA on glycophagy and glycolysis.Finally,simultaneous inhibition of glycophagy and mitophagy abolished the cardioprotective effects and energy regulation of AA.These results demonstrate that AA protects ischemic cardiomyocytes by modulating glycophagy- and mitophagy-based energy metabolism through the PI3K/Akt and AMPK pathways.
登录
查看更多内容
影响因子：
6
作者：
M. Lorentzon;T. Råmunddal;E. Bollano;B. Soussi;F. Waagstein;E. Omerovic
通讯作者：
M. Lorentzon;T. Råmunddal;E. Bollano;B. Soussi;F. Waagstein;E. Omerovic
AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
21.3
作者：
通讯作者：
--
DOI：
10.1016/j.bbrc.2011.08.106
发表时间：
2011-09-30
影响因子：
3.1
作者：
Jiang, Sixin;Wells, Clark D.;Roach, Peter J.
通讯作者：
Roach, Peter J.
DOI：
--
发表时间：
1999-06
期刊：
European journal of dermatology : EJD
影响因子：
--
作者：
F. Maquart;F. Chastang;Alain Siméon;P. Birembaut;P. Gillery;Y. Wegrowski
通讯作者：
F. Maquart;F. Chastang;Alain Siméon;P. Birembaut;P. Gillery;Y. Wegrowski