Protective effect of icotinib on right ventricular remodeling in pulmonary hypertension rats
Objective To investigate the effect of icotinib on right ventricular remodeling in rats with monocrotaline(MCT)-induced pulmonary hypertension(PH).Methods Sprague-Dawley rats were randomly divided into control group(0.3％sodium carboxymethyl cellulose),model group and low,high dose experimental groups(30,60 mg·kg-1 icotinib),8 rats in each group.PH rat model was established by single intraperitoneal injection of 60 mg·kg-1 MCT in model group and low,high dose experimental groups.The drug was administered continuously for 4 weeks after MCT injection.The hemodynamic indexes of each group were detected.Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling(TUNEL)staining was used to detect the apoptosis of right ventricular cardiomyocytes.The protein levels of B cell lymphoma-2(Bcl-2),Bcl-2 associated X protein(Bax),cleaved cysteine aspartic acid specific protease-3(cleaved-caspase-3),epidermal growth factor receptor(EGFR),phosphorylated EGFR(p-EGFR),optic atrophy 1(Opa1)and mitofusin 2(Mfn2)were detected by Western blot analysis.Results The right ventricular systolic pressure in low,high dose experimental groups and control group,model group were(38.58±4.98),(34.15±3.88),(23.66±2.45)and(45.07±5.78)mmHg;the mean pulmonary artery pressure were(27.85±3.77),(24.25±3.09),(17.33±2.46)and(33.07±4.15)mmHg;the right ventricle(RV)to left ventricle+septum were(36.38±5.51)％,(33.63±4.69)％,(22.25±2.96)％and(42.50±7.33)％;the RV to tibial length were(69.33±7.86),(62.69±7.17),(49.12±6.42)and(78.22±9.07)mg·cm-1.There were significant differences in the above indexes between low,high dose experimental groups and model group(all P＜0.01).There were significant differences in Bcl-2,Bax,cleaved caspase-3,p-EGFR,Opa1,Mfn2 between low,high dose experimental groups and model group(P＜0.05,P＜0.01).Conclusion Icotinib can inhibit right ventricular remodeling in PH rats induced by MCT,and its mechanism may be related to reducing the phosphorylation level of EGFR in the right ventricle,alleviating mitochondrial dysfunction and inhibiting cardiomyocyte apoptosis.
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