Abstract
AimsTo investigate whether dexmedetomidine (DEX) preconditioning could alleviate the inflammation caused by myocardial ischemia/reperfusion (I/R) injury by reducing HMGB1-TLR4-MyD88-NF-кB signaling.MethodsSeventy 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 in serum and myocardium were quantified by enzyme-linked immunosorbent assay, and expression of HMGB1, TLR4, MyD88, IκB and NF-κB in the myocardial I/R area were determined with Western blot and immunocytochemistry.ResultsMyocardial infarct sizes, histological scores, levels of circulating and myocardial IL-6 and TNF-α, the expression of HMGB1, TLR4, MyD88 and NF-κB, and the degradation of IκB were 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 (P<0.01 vs. I/R group). Similarly, the serum and myocardial levels of IL-6 and TNF-α, the expression of HMGB1, TLR4, MyD88 and NF-κB, and the degradation of IκB were significantly reduced in the DEX group (P<0.01 vs. I/R group). These effects were partly reversed by yohimbine, a selective α2-adrenergic receptor antagonist, while yohimbine alone had no significant effect on any of the above indicators.ConclusionDEX preconditioning reduces myocardial I/R injury in part by attenuating inflammation, which may be attributed to the downregulation of the HMGB1-TLR4-MyD88-NF-кB signaling pathway mediated by the α2-adrenergic receptor activation.
Highlights
In the ischemic heart, coronary reperfusion can effectively limit infarct size
Myocardial infarct sizes, histological scores, levels of circulating and myocardial interleukin 6 (IL-6) and TNF-α, the expression of high mobility group box-1 (HMGB1), Toll-like receptor 4 (TLR4), MyD88 and NF-κB, and the degradation of IκB were significantly increased in the I/R group compared with the sham group (P
The serum and myocardial levels of IL-6 and TNF-α, the expression of HMGB1, TLR4, MyD88 and NF-κB, and the degradation of IκB were significantly reduced in the DEX group (P
Summary
Coronary reperfusion can effectively limit infarct size. A variety of cytokines such as tumor necrosis factor α (TNFα) and interleukin 6 (IL-6) are released, triggering excessive regional inflammatory responses and provoking further myocardial damage. A number of studies have shown that inhibition of excessive inflammation reduced infarct size and ameliorated heart dysfunction induced by I/R injury [3,4,5]. Toll-like receptor 4 (TLR4) has been identified as a mediator of inflammation and organ injury in several I/R models including cerebral I/R, liver I/R and myocardial I/R [6,7,8]. Activation of TLR4 promotes the activity of NF-κB through a MyD88-dependent pathway, which triggers the expressions of proinflammatory cytokines including IL-1, IL-6, and TNF-α, leading to further tissue damage [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
