Dexmedetomidine Preconditioning Attenuates Myocardial Ischemia/reperfusion Injury By Down-regulating The HMGB1/TLR4/NF-κB Signaling Pathway In Rats

Part One: Dexmedetomidine preconditioning reduces the levels of IL-6 and TNF-αObjective To observe the effect of dexmedetomidine(Dex) preconditioning on the levels of IL-6 and TNF-α after myocardial ischemia/reperfusion(I/R) injury.Methods Sixty-five rats were randomly assigned into five groups: sham group,myocardial I/R group(I/R), Dex+I/R group(DEX), Dex+yohimbine+I/R group(DEX/YOH), and yohimbine+I/R group(YOH). Animals were subjected to 30 min of ischemia induced by occluding the left anterior descending artery followed by 120 min of reperfusion. Myocardial infarct size and histological scores were evaluated. The levels of IL-6 and TNF-α were quantified by enzyme-linked immunosorbent assay(ELISA) in serum and myocardial tissues.Results Myocardial infarct sizes, histological scores and levels of IL-6 and TNF-αwere significantly increased in the I/R group compared with the sham group(P<0.01). Dex preconditioning significantly reduced the myocardial infarct size and histological scores caused by I/R(P<0.01 vs. I/R group). Similarly, the levels of IL-6 and TNF-α were significantly reduced in the DEX group(P<0.01 vs. I/R group). All the reductions were partly reversed by yohimbine, a selective α2-adrenergic receptor antagonist, while yohimbine alone had no significant effects on any of the above indicators.Conclusion Dex preconditioning significantly reduces the levels of IL-6 and TNF-αduring myocardial I/R injury.Part Two: Effect of dexmedetomidine preconditioning on HMGB1/TLR4/NF-кB signaling pathway and its mechanismObjective To investigate whether Dex preconditioning could alleviate the inflammation after myocardial ischemia/reperfusion(I/R) injury via mediating the HMGB1/TLR4/NF-кB signaling pathway.Methods Forty rats were randomly assigned into five groups: sham group, myocardial I/R group(I/R), Dex+I/R group(DEX), Dex+yohimbine+I/R group(DEX/YOH), and yohimbine+I/R group(YOH). Animals were subjected to 30 min of ischemia induced by occluding the left anterior descending artery followed by 120 min of reperfusion. The myocardial expressions of HMGB1, TLR4, MyD88 and NF-κB in I/R area were determined with Western blot and immunocytochemistry analysis.Results The expressions of HMGB1, TLR4, MyD88 and NF-κB were significantly increased in the I/R group compared with the sham group(P<0.01). Dex preconditioning significantly reduced the expressions of HMGB1, TLR4, MyD88, and NF-κB in the DEX group(P<0.01 vs. I/R group). All the reductions were partly reversed by yohimbine, a selective α2-adrenergic receptor antagonist, while yohimbine alone had no significant effects on any of the above indicators.Conclusion Dex preconditioning reduces myocardial I/R injury in part by attenuating the inflammatory effects, which may be attributed to the down-regulating of the HMGB1/TLR4/NF-кB signaling pathway mediated by the α2-adrenergic receptor activation.