Effects of Kuoxin Formula regulating ASK1/JNK/Cx43 signaling pathway on cardiomyocyte apoptosis in rats with doxorubicin-induced dilated cardiomyopathy
Objective To observe the effect of Kuoxin Formula on improving myocardial cell apoptosis in rats with doxorubicin-induced dilated cardiomyopathy(DCM)and to explore its underlying mechanism.Methods 68 Wistar rats were selected for the experiment,8 of them were set as the blank control group(Control group),and the remaining 60 were randomly divided into the model group(Model group),Kuoxin Formula low dose(KXF-L group),Kuoxin Formula middle dose(KXF-M group),Kuoxin Formula high dose(KXF-H group,positive control drug captopril group(Captopril group)after intraperitoneal injection of doxorubicin to establish a DCM mod-el.12 rats in each group,continuous infusion Stomach 4 weeks.After treatment,echocardiography was performed to measure myocardial remodeling and changes in cardiac function;HE staining was used to observe morphological changes in myocardial tissue;immunohisto-chemistry was used to observe Cx43 expression in myocardial tissue;western-blot method was used to measure Bax,Bel-2,Caspase-9,p-ASK1,p-JNK,p-Cx43,ASK1,JNK,and Cx43 protein expression in myocardial tissue.Results ①Echocardiography:Com-pared with the Control group,the Model groups LVEF and LVFS were significantly reduced(P＜0.01),and LVEDD and LVESD were significantly increased(P＜0.01).After the intervention of Kuoxin Formula,LVEF,LVFS,LVEDD and LVESD were improved com-pared with before(P＜0.01).②HE staining:Compared with the Control group,the Model group had cardiomyocyte hypertrophy,inter-stitial proliferation,and disordered cell arrangement.The above pathological changes were significantly improved after the intervention of Kuoxin Formula.③Immunohistochemistry:Compared with the Control group,the expression of Cx43 in the Model group was significant-ly reduced,and improved after treatment with Kuoxin Formula;4.Western-Blot:Compared with the Control group,the protein expres-sions of p-Cx43 and Cx43 in the Model group were significantly reduced(P＜0.01)while p-JNK and p-ASK1 were significantly in-creased(P＜0.01).After the intervention of Kuoxin Formula,The protein expression of p-Cx43 in the medium and high dose groups of Kuoxin Formula increased significantly(P＜0.05).Meanwhile,the protein expression of Cx43 in all dose groups of Kuoxin Formula increased significantly(P＜0.01)while p-JNK and p-ASK1 were both significant decrease(P＜0.01).Conclusion The traditional Chinese medicine Kuanxin Formula can alleviate myocardial remodeling in rats with dilated cardiomyopathy induced by doxorubicin,and its mechanism is related to regulating the ASK1/JNK/Cx43 signaling pathway to improve gap junction-mediated cardiomyocyte apopto-sis.
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