Mechanism of carvedilol against myocardial ischemia/reperfusion injury / 医学研究生学报

ABSTRACT

Objective Carvedilol (Cvd) has a potential cardioprotective effect against myocardial ischemia/reperfusion (I/R) injury but its molecular mechanism is not yet clarified. The present study aimed to investigate whether the mechanism of Cvd against myocardial I/R injury-induced cardiomyocyte apoptosis is associated with its protection of the myocardium by modulating the unfolded protein response (UPR).Methods Forty male SD rats were randomly divided into five groups of equal number, sham operation, I/R, I/R + UPR agonist dithiothreitol (I/R+DTT), I/R + DTT with Cvd pretreatment at 5 mg/kg (I/R+DTT+Cvd), and I/R with Cvd pretreatment at 5 mg/kg (I/R+Cvd). The myocardial infarct size (infarct area / area-at-risk, IA/AAR) was measured by TCC & Evans blue double staining, the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) detected by echocardiography, the apoptosis of the myocardiocytes determined by TUNEL staining, the activation of the UPR signaling pathway and the expressions of Caspase-12 and Casoase-3 detected by Western blot, and the concentrations of LDH and CK-MB assayed with the detection kit, followed by a comprehensive evaluation of the effects of Cvd on myocardial I/R injury.Results Myocardial IA/AAR was significantly increased in the I/R+DTT group as compared with the sham operation control (\[54.1±3.28\] % vs \[24.25±3.19\] %, P<0.05), higher in the I/R+DTT and I/R+DTT+Cvd (P<0.05) but lower in the I/R+Cvd than in the I/R group (P<0.05), and lower in the I/R+DTT+Cvd than in the I/R+DTT group (P<0.05). In comparison with the sham operation control, all the other four groups showed significantly decreased LVEF and LVFS (P<0.05), both remarkably lower in the I/R+DTT (\[44.5±1.56\] % and \[19.2±2.23\] %) than in the I/R group (\[61.5±2.63\] % and \[28.4±1.42\] %) (P<0.05), but higher in the I/R+DTT+Cvd and I/R+Cvd groups (P<0.05). The apoptosis rate of the cardiomyocytes was markedly increased in the I/R, I/R+DTT, I/R+DTT+Cvd, and I/R+Cvd groups as compared with that in the sham operation control (\[24.4±2.65\]%, \[48.3±1.62\]%, \[32.6±1.28\] % and \[13.2±2.21\]% vs \[6.2±1.27\]%, P<0.05), higher in the I/R+DTT and I/R+DTT+Cvd (P<0.05) but lower in the I/R+Cvd than in the I/R group (P<0.05). Compared with the sham operation control, the other four groups exhibited significantly elevated levels of expressions of the GRP78, CHOP and ATF6 proteins (P<0.05), all markedly higher in the I/R+DTT (P<0.05) but lower in the I/R+Cvd (P<0.05) and that of GRP78 lower in the I/R+DTT+Cvd than in in the I/R group (P<0.05), and all lower in the I/R+DTT+Cvd than in the I/R+DTT group (P<0.05).Conclusion Carvedilol can significantly alleviate the apoptosis of cardiomyocytes, and its molecular mechanism is related to its inhibitory effect on the UPR pathway.