Sevoflurane postconditioning protects against myocardial ischemia/reperfusion injury by restoring autophagic flux via an NO-dependent mechanism

Authors: Shi-gang Qiao1,2,3, Ying Sun4, Bo Sun4, An Wang1,4, Jia Qiu1,4, Lei Hong2, Jian-zhong An2, Chen Wang2,3, Hui-ling Zhang1
1 Department of Pharmacology and Laboratory of Cerebrovascular and Cardiovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China
2 Institute of Clinical Medicine Research, the Affiliated Suzhou Hospital of Nanjing Medical University; Suzhou Science and Technology Town Hospital, Suzhou 215153, China
3 Department of Anesthesiology and Perioperative Medicine, the Affiliated Suzhou Hospital of Nanjing Medical University; Suzhou Science and Technology Town Hospital, Suzhou 215153, China
4 Department of Anesthesiology, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China
Correspondence to: Shi-gang Qiao:, Chen Wang:, Hui-ling Zhang:,
DOI: 10.1038/s41401-018-0066-y
Received: 14 December 2017
Accepted: 5 June 2018
Advance online: 12 July 2018


Volatile anesthetics improve postischemic cardiac function and reduce infarction even when administered for only a brief time at the onset of reperfusion. A recent study showed that sevoflurane postconditioning (SPC) attenuated myocardial reperfusion injury, but the underlying mechanisms remain unclear. In this study, we examined the effects of sevoflurane on nitric oxide (NO) release and autophagic flux during the myocardial ischemia/reperfusion (I/R) injury in rats in vivo and ex vivo. Male rats were subjected to 30 min ischemia and 2 h reperfusion in the presence or absence of sevoflurane (1.0 minimum alveolar concentration) during the first 15 min of reperfusion. We found that SPC significantly improved hemodynamic performance after reperfusion, alleviated postischemic myocardial infarction, reduced nicotinamide adenine dinucleotide content loss, and cytochrome c release in heart tissues. Furthermore, SPC significantly increased the phosphorylation of endothelial nitric oxide synthase (NOS) and neuronal nitric oxide synthase, and elevated myocardial NOS activity and NO production. All these effects were abolished by treatment with an NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.v.). We also observed myocardial I/R-induced accumulation of autophagosomes in heart tissues, as evidenced by increased ratios of microtubule-associated protein 1 light chain 3 II/I, up-regulation of Beclin 1 and P62, and reduced lysosome-associated membrane protein-2 expression. SPC significantly attenuated I/R-impaired autophagic flux, which were blocked by L-NAME. Moreover, pretreatment with the autophagic flux blocker chloroquine (10 mg/kg, i.p.) increased autophagosome accumulation in SPC-treated heart following I/R and blocked SPC-induced cardioprotection. The same results were also observed in a rat model of myocardial I/R injury ex vivo, suggesting that SPC protects rat hearts against myocardial reperfusion injury by restoring I/R-impaired autophagic flux via an NO-dependent mechanism.
Keywords: myocardial reperfusion injury; autophagy; nitric oxide; nitric oxide synthase; sevoflurane; NG-nitro-L-arginine methyl ester; chloroquine

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