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 Ml 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 Ml 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 further promoted 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.

Fan Qiu;Yi Yuan;Wei Luo;Yan-shan Gong;Zhong-ming Zhang;Zhong-min Liu;Ling Gao

Translational Medical Center for Stem Cell Therapy&Institute for Regenerative Medicine,Shanghai East Hospital,Tongji University School of Medicine,Shanghai 200123,China;Department of Cardiovascular and Thoracic Surgery,Shanghai East Hospital,Tongji University School of Medicine,Shanghai 200120,China;Department of Cardiovascular and Thoracic Surgery,Affiliated Hospital of Xuzhou Medical University,Xuzhou 221006,China;Shanghai Institute of Stem Cell Research and Clinical translation,Shanghai East Hospital,Tongji University,Shanghai 200120,China;Shanghai Engineering Research Center for Stem Cell Clinical Treatment,Shanghai 200123,China

中国药理学报（英文版）

[1]Fan Qiu;Yi Yuan;Wei Luo;Yan-shan Gong;Zhong-ming Zhang;Zhong-min Liu;Ling Gao-.Asiatic acid alleviates ischemic myocardial injury in mice by modulating mitophagy-and glycophagy-based energy metabolism)[J].中国药理学报（英文版）,2022(06):1395-1407

glycophagy,Cytosolic,pentacyclic,Centella,phosphocreatine,mitophagosomes,colocalization,ODG,STBD1,GSK690693

Asiatic,alleviates,ischemic,myocardial,injury,mice,by,modulating,mitophagy,energy,metabolism,Myocardial,infarction,MI,causes,disturbances,ultimately,leading,poor,prognosis,glycogen,autophagy,mitochondrial,are,upregulated,Ml,optimize,but,limited,extent,AA,triterpene,derived,from,traditional,Chinese,herb,asiatica,displays,inflammatory,antioxidant,antiapoptotic,activities,has,been,found,focal,cerebral,liver,reversing,dysfunction,In,this,study,investigated,whether,exerted,cardioprotective,effects,against,activating,balance,vitro,were,examined,neonatal,mouse,cardiomyocytes,subjected,oxygen,glucose,deprivation,Treatment,significantly,increased,viability,improved,evidenced,ATP,level,vivo,studied,model,Administration,reduced,size,cardiac,treatment,also,promoted,relieved,edema,number,myocardium,light,chain,LC3,treated,Mitophagy,activation,was,accompanied,AMPK,signaling,Knockdown,abolished,activated,Furthermore,showed,that,OGD,starch,binding,domain,protein,type,receptor,associated,like,GABARAPL1,interaction,extracellular,acidification,whereas,further,PI3K,Akt,inhibitor,LY294002,blocked,glycolysis,Finally,simultaneous,inhibition,regulation,These,results,demonstrate,protects,through,pathways

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