Role of Keap1-Nrf2/ARE signal transduction pathway in protection of dexmedetomidine preconditioning against myocardial ischemia/reperfusion injury

Objective: To explore the role and mechanism of the Kelch sample related protein-1-nuclear factor erythroid-2 related factor 2/antioxidant response element (Keap1-Nrf2/ARE) signaling pathway in protection of dexmedetomidine (DEX) preconditioning against myocardial ischemia/reperfusion injury (MIRI). Methods: A total of 70 male SD rats were randomly divided into seven equal groups (n=10): blank control (S group), ischemia/reperfusion injury (C group), DEX preconditioning (DEX group), tertiary butylhydroquinone (tBHQ) control (tBHQ group), combined tBHQ and DEX preconditioning (tBHQ+DEX group), all-trans retinoic acid (ATRA) control (ATRA group), and combined ATRA and DEX preconditioning (ATRA+DEX group). Serum creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) concentrations were measured by ELISA kits, and the infarct size (IS) was assessed by Evan’s blue and 2,3,5-triphenyltetrazolium chloride (TTC) staining. Oxidative stress was assessed through Western blotting for expression of Keap1-Nrf2/ARE pathway members and oxidative stress markers. Results: Cardioprotection of DEX, tBHQ, and tBHQ+DEX preconditioning treatments were shown as lower concentrations of serum CK-MB and cTnI and a smaller IS following MIRI in rats compared with those of MIRI rats without pre-treatment. In addition, tBHQ+DEX preconditioning exhibited stronger myocardial protection compared with DEX preconditioning. Mechanistically, the cardioprotection offered by DEX, tBHQ, and tBHQ+DEX preconditioning treatments was mediated via exerting antioxidant stress through activation of the Keap1-Nrf2/ARE signal transduction pathway. Conversely, the protective effects of DEX were diminished by blocking the Keap1-Nrf2/ARE pathway with inhibitor ATRA. Conclusion: DEX preconditioning protects against MIRI by exerting antioxidant stress through activation of the Keap1-Nrf2/ARE signal transduction pathway, while inhibition of the Keap1-Nrf2/ARE signal transduction pathway reverses the protective effect of DEX preconditioning on MIRI.     

MicroRNA‐153‐3p increases autophagy in sevoflurane‐preconditioned mice to protect against ischaemic/reperfusion injury after knee arthroplasty

The use of tourniquet during total knee arthroplasty (TKA) can result in ischaemia/reperfusion injury (IRI). Of interest, microRNAs (miRs) are reported to be involved in various kinds of IRI due to their ability in modulating autophagy. Therefore, the study aimed to investigate the effect of miR‐153‐3p on autophagy in IRI in vitro and in vivo under sevoflurane preconditioning. In the in vitro model, chondrocytes from naive mice were treated with 0% FBS alone or in combination with sevoflurane. Additionally, in vivo assays were conducted in mouse models with tourniquet‐induced IRI after TKA under or without sevoflurane preconditioning. The pathological observation in vivo validated that sevoflurane preconditioning protected the knee joint against IRI. Moreover, miR‐153‐3p expression was diminished in chondrocytes of the in vitro model and in cartilage tissue of the in vivo model, but its expression was appreciably up‐regulated in the presence of sevoflurane preconditioning. Mechanistic study showed that miR‐153‐3p disrupted the interaction between Bcl‐2 and Beclin1 by targeting Bcl‐2, thereby facilitating autophagy in chondrocytes under sevoflurane preconditioning. Furthermore, the experiments in human chondrocytes also verified the protective effects of miR‐153‐3p against IRI were realized through inhibiting Bcl‐2. Collectively, miR‐153‐3p overexpression blocks the interaction between Bcl‐2 and Beclin1 via down‐regulation of Bcl‐2 to promote autophagy of chondrocytes, thus protecting knee joint against IRI after TKA under sevoflurane preconditioning.