Dexmedetomidine preconditioning may attenuate myocardial ischemia/reperfusion injury by down-regulating the HMGB1-TLR4-MyD88-NF-кB signaling pathway.

Abstract

AIMS:

To 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.

METHODS:

Seventy 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.

RESULTS:

Myocardial 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.

CONCLUSION:

DEX 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.

• Authors: Jing-Jing Zhang, Ke Peng, Juan Zhang, Xiao-Wen Meng, Fu-Hai Ji
• Journal: PloS one (PLoS One) Vol. 12 Issue 2 Pg. e0172006 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 28222157 (Publication Type: Journal Article)

Chemical References

• Adrenergic alpha-2 Receptor Agonists
• HMGB1 Protein
• Hbp1 protein, rat
• Myd88 protein, rat
• Myeloid Differentiation Factor 88
• NF-kappa B
• Tlr4 protein, rat
• Toll-Like Receptor 4
• Dexmedetomidine

Topics

• Adrenergic alpha-2 Receptor Agonists (therapeutic use)
• Animals
• Dexmedetomidine (therapeutic use)
• Down-Regulation
• Enzyme-Linked Immunosorbent Assay
• HMGB1 Protein (physiology)
• Male
• Myeloid Differentiation Factor 88 (physiology)
• Myocardial Ischemia (metabolism, prevention & control)
• Myocardial Reperfusion Injury (metabolism, prevention & control)
• NF-kappa B (physiology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Toll-Like Receptor 4 (physiology)