Dexmedetomidine mitigates myocardial ischemiareperfusion injury via regulation of HMGB1-TLR4-NF-κB signaling axis

Ting Wen,Ia Liu,Chaxiu Yu,Gan Li,Benchao Hou,Shibiao Chen

doi:10.4314/tjpr.v20i11.6

Abstract

Purpose: To study the effect of dexmedetomidine (Dex) on myocardial ischemia-reperfusion injury (MIRI), and the associated mechanism of action.Methods: Sixty Sprague-Dawley (SD) rats were assigned to sham, ischemia-reperfusion (I/R), Dex, and MD groups (methyllycaconitine prior to injection with Dex), with 15 rats in each group. Pathological changes in myocardial tissues were determined in all groups. Protein expression levels of HMGB1, TLR4, NF-κB and myeloid differentiation protein 88 (MyD88) in serum and myocardial tissues were assayed and compared.Results: Protein levels of HMGB1, TLR4, MyD88 and NF-κB were significantly higher in heart muscle I/R rats than those in sham group, but lower in heart muscle of rats in Dex group than in heart muscle of I/R rats (p < 0.05). However, they were significantly up-regulated in MD group, relative to Dex group (p< 0.05).Conclusion: Dex exerts a protective effect against ischemia/reperfusion-induced myocardial damage via HMGB1-TLR4-NF-κB signal axis via CAP, and thus, is a potential agent for the management of myocardial disease.

Highlights

Myocardial ischemia reperfusion injury (MIRI) is a major cause of severe postoperative complications and death in patients undergoing coronary artery reconstruction [1]
It is recognized that cholinergic antiinflammatory pathway (CAP) is the main route
Clinical investigations have demonstrated that MIRI induces inflammatory cascade through the activation of HMGB1 protein, which causes myocardial tissue damage

Summary

INTRODUCTION

Myocardial ischemia reperfusion injury (MIRI) is a major cause of severe postoperative complications and death in patients undergoing coronary artery reconstruction [1]. CAP has been gradually applied in the protection of organs such as heart, liver and kidney from ischemia-reperfusion injury, through a mechanism involving blockage of the inflammatory pathway by activating alpha nicotinic acetylcholine receptor (α7nAchR) [4,5]. Clinical investigations have demonstrated that MIRI induces inflammatory cascade through the activation of HMGB1 protein, which causes myocardial tissue damage. HMGB1 binds to Toll-like receptor 4 (TLR4) and activates NF-κB mediated by myeloid differentiation factor 88 (MyD88) and Toll interleukin receptor-related regulatory molecules. This in turn, induces the nuclear transfer of NF-κB and IRF-3, as well as regulation of the expressions of related cytokines, eventually impairing myocardial systolic function, leading to myocardial tissue damage [6,7].

Study design

RESULTS

DISCUSSION

Conflict of interest