Abstract:

Objective To discuss the protective effect of dexmedetomidine （Dex） on myocardial ischemia/reperfusion injury （MIRI） in the rats， and to clarify its mechanism. Methods Forty-eight SD rats were randomly divided into control group， model group， Dex group， and Dex+Compound C group， with 12 rats in each group. The MIRI model was established by ligation of left anterior descending coronary artery. Echocardiography was used to evaluate the cardiac function of the rats in various groups； HE staining was used to observe the pathomorphology of myocardium tissue of the rats in various groups； kits were used to detect the serum level of cardiac troponin I （cTnI） and the activities of hexokinase （HK）， phosphofructokinase （PFK）， and pyruvate kinase （PKM） of the rats in various groups； high performance liquid chromatography （HPLC） was used to detect the levels of myocardial energy metabolites adenosine triphosphate （ATP）， adenosine diphosphate （ADP）， and adenosine monophosphate （AMP） in myocardium tissue of the rats in various groups， and the energy charge （EC） was calculated； immunohistochemistry and Western blotting method were used to detect the expressions of Toll-like receptor 4 （TLR4）， macrophage migration inhibitory factor （MIF）， AMP-activated protein kinase（AMPK） and phosphorylated AMPK （p-AMPK） proteins in myocardium tissue of the rats in various groups. Results Compared with control group， the left ventricular ejection fraction （EF）， fractional shortening （FS）， cardiac output （CO）， and stroke volume （SV） of the rats in model group were significantly decreased （P<0.05）； the serum level of cTnI was significantly increased （P<0.05）， and the activities of HK， PFK， and PKM were significantly decreased （P<0.05）； the levels of ATP and ADP and EC in myocardium tissue were significantly decreased （P<0.05）， while the level of AMP was significantly increased （P<0.05）； the expression levels of TLR4 and MIF proteins in myocardium tissue were increased （P<0.05）， and the p-AMPK/AMPK ratio was decreased （P<0.05）. Compared with model group， the EF， FS， CO， and SV of the rats in Dex group were significantly increased （P<0.05）； the serum level of cTnI was significantly decreased （P<0.05）， and the activities of HK and PKM were significantly increased （P<0.05）； the levels of ATP and ADP and EC in myocardium tissue were significantly increased （P<0.05）； the expression levels of TLR4 and MIF proteins in myocardium tissue were decreased （P<0.05）， and the p-AMPK/AMPK ratio was increased （P<0.05）. Compared with Dex group， the EF， FS， CO， and SV of the rats in Dex+Compound C group were significantly decreased （P<0.05）， the serum level of cTn I was increased （P<0.05）， and the PKM activity was decreased （P<0.05）； the levels of ATP and ADP and EC in myocardium tissue were significantly decreased （P<0.05）； the expression levels of TLR4 and MIF proteins in myocardium tissue were increased （P<0.05）， and the p-AMPK/AMPK ratio was decreased （P<0.05）. Conclusion Dex improves the imbalance of myocardial energy metabolism and myocardial dysfunction after MIRI by inhibiting TLR4/MIF signaling and activating AMPK phosphorylation. Its therapeutic effect can be antagonized by the AMPK inhibitor Compound C； Dex plays the cardioprotective effect by regulating the TLR4/MIF/AMPK signaling pathway.

Key words: Dexmedetomidine, Myocardial ischemia-reperfusion injury, Toll-like receptor 4, Energy metabolism, Adenosine monophosphate-activated protein kinase