Effect of phosphoglycogen synthase kinase-3 β induced by low dose of tunicamycin on mitochondrial permeability transition pore in ischemia-reperfusion myocardium

Abstract

Objective To evaluate the effect of glycogen synthase kinase-3beta (GSK-3β) activity on mitochondrial permeability transition pore (mPTP) in the protective effects of preconditioning with endoplasmic reticulum stress (ERS) induced by low dose of tunicamycin (TM) against myocardial ischemia reperfusion (I/R) injury. Methods Forty adult male sprague-dawley rats were randomly divided into four groups: Sham, TM (Rats were treatmented by TM 0.6 mg/kg at 30 min before model established), I/R, and TM+ LY [Rats were treatmented by TM 0.6 mg/kg and protein kinase B (Akt) inhibitor LY294002 10 mg/kg]. The model of I/R were established by occlusion of left anterior descending coronary artery for 0.5 h followed by reperfusion for 2 h. Hemodynamic parameters were recorded after coronary artery perforation, 1 h and 2 h after reperfusion. After 2 hours of reperfusion, the expression of phosphorylated Akt (p-Akt), p-GSK-3β and the openness of mPTP were detected in the hearts. Results Compared with base line, left ventricular systolic pressure (LVSP), maximum rate of increase or decrease of left ventricular pressure (±dp/dt max) decreased, and left ventricular end-diastolic pressure (LVEDP)increased in I/R group, TM group and TM+ LY group, while the change was more significantly in I/R group. The expression of p-Akt and p-GSK-3 beta protein in TM and TM+ LY group was higher than that in I/R group, and the expression of p-Akt and p-GSK-3β protein in TM+ LY group was lower than that in TM group. At 2 hours after reperfusion, degree of variation of absorbance value (ΔA) of the mPTP of Sham, I/R, TM and TM+ LY group were (78.9±9.2)%, (36.1±4.8)%, (61.4±8.3)% and (46.3 ±5.2)%. The ΔA of TM group was larger than that of I/R group (t=3.280, P<0.01). Compared with TM group, the ΔA of TM+ LY group was relatively small (t=2.720, P<0.01). Conclusion The protective effect of preconditioning with ERS induced by low dose TM is related to the inhibition of mPTP opening by regulating GSK-3β activity. Key words: Myocardial ischemia reperfusion injury; Endoplasmic reticulum stress; Preconditioning; Glycogen synthase kinase-3β; Mitochondrial permeability transition pore