Crocin-Elicited Autophagy Rescues Myocardial Ischemia/Reperfusion Injury via Paradoxical Mechanisms.
Crocin, the main effective component of saffron, exerts protective effects against ischemia/reperfusion injury during strokes. However, the effects of crocin in myocardial ischemia/reperfusion injury, and the mechanisms involved, remain unknown. Pretreated with crocin for 7 days, C57BL/6N mice were subjected to 30 min of myocardial ischemia followed by 12[Formula: see text]h of reperfusion (for cardiac function and infarct size, cell apoptosis and necrosis). Neonatal mouse cardiomyocytes were subjected to 2 h of hypoxia followed by 4 h of reoxygenation. NMCM's survival was assessed during hypoxia and reoxygenation in the presence or absence of the autophagy inhibitor 3-methyladenine or the inducer rapamycin. Western blotting was used to evaluate AMPK, Akt, and autophagy-related proteins. Autophagosome was observed using electron microscopy. In the in vivo experiment, crocin pretreatment significantly attenuated infarct size, myocardial apoptosis and necrosis, and improved left ventricular function following ischemia/reperfusion. In vitro data revealed that autophagy was induced during hypoxia, the levels of which were intensely elevated during reoxygenation. Crocin significantly promoted autophagy during ischemia, accompanied with the activation of AMPK. In contrast, crocin overtly inhibited autophagy during reperfusion, accompanied with Akt activation. Induction and inhibition of autophagy mitigated crocin induced protection against NMCMs injury during hypoxia and reoxygenation, respectively. Our data suggest that crocin demonstrated a myocardial protective effect via AMPK/mTOR and Akt/mTOR regulated autophagy against ischemia and reperfusion injury, respectively.
* Department of Cardiology, No. 421 Hospital of PLA, Guangzhou, P.R. China.
Chao
C
Zeng
† Department of Cardiology, No. 422 Hospital of PLA, Zhanjiang, P.R. China.
Hu
H
Li
* Department of Cardiology, No. 421 Hospital of PLA, Guangzhou, P.R. China.
Zhiwen
Z
Fan
* Department of Cardiology, No. 421 Hospital of PLA, Guangzhou, P.R. China.
Lei
L
Zhong
* Department of Cardiology, No. 421 Hospital of PLA, Guangzhou, P.R. China.
Zhen
Z
Guo
* Department of Cardiology, No. 421 Hospital of PLA, Guangzhou, P.R. China.
Yaping
Y
Guo
* Department of Cardiology, No. 421 Hospital of PLA, Guangzhou, P.R. China.
Yusheng
Y
Xi
D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics*; D002338:Carotenoids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000209:etiology* / Q000628:therapy*; D032383:Myocytes, Cardiac; D008517:Phytotherapy; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
D002338:Carotenoids; C029036:crocin; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
Apoptosis; Autophagy; Cardiomyocytes; Crocin; Myocardial Ischemia/Reperfusion