Action Mechanism of Zhenwu Decoction on Regulating Mitochondrial Energy Metabolism and Improving Myocardial Cell Damage in Chronic Heart Failure Based on the PPARα/ASCL1 Signaling Pathway

WANG Mengni; XU Shiqiang; QIN Yanmi; YAO Cankun; XIE Tian; ZHANG Tianfeng

Abstract：Objective To explore the effects of Zhenwu decoction on the mitochondrial structure as well as PPARα/ACSL1 signaling pathway in rats model of doxorubicin induced chronic heart failure(CHF).Methods CHF rats model were constructed by tail vein injection of doxorubicin.Then they were randomly divided into model group,Zhenwu decoction group,trimetazidine hydrochloride group,Zhenwu decoction plus trimetazidine hydrochloride group,and the normal rats injected with 0.9%saline via the tail vein as the control group.After successful modeling,each group was intervened with corresponding drugs by gavage for 6 weeks,and the general condition of the rats was observed,the heart-to-body ratio was calculated.Color Doppler ultrasound imager was used to detect cardiac function in rats.Hematoxylin-eosin(HE)staining and Masson staining were used to observe the changes in cardiology.Elisa was used to detect BNP content in rat hearts.Transmission electron microscopy(TEM)was used to observe the changes in mitochondrial structure in rat hearts.Cardiac transcriptomics was used to analyze the differential genes,and the enrichment analysis of GO,KEGG and GSEA was performed.Western blot and RT-qPCR were used to detect the protein and mRNA expression of PPARα and ACSL1.Results Compared with the control group,the general condition of the model group was poor,the pathological damage of myocardial tissue was obvious,the area of myocardial fibrosis increased,and the mitochondrial structure of the heart was seriously damaged in the model group rats.The heart-to-body ratio decreased,the left ventricular short-axis shortening rate(LVFS)and left ventricular ejection fraction(LVEF)were significantly reduced,while the serum BNP content was significantly increased(P<0.05)in the model group rats.Transcriptomic results showed that PPAR signaling pathway was an important pathway regulating energy metabolism in the pathological mechanism of CHF.After experimental verification,it was found that compared with the normal group,the expression of PPARα and ACSL1 in the myocardium of the model group decreased at both the protein and mRNA level(P<0.05).Compared with the model group,the Zhenwu decoction group and Zhenwu decoction plus trimetazidine hydrochloride group showed improvements in general conditions,pathological damage,mitochondrial structure,etc.,with increased LVFS and LVEF(P<0.05)and decreased BNP content(P<0.05)in rats.And the expression of PPARα and ACSL1 increased at both protein and mRNA levels(P<0.05).Conclusion Through transcriptomics and enrichment analysis,it was concluded that PPAR signaling pathway is an important signaling pathway in the pathological mechanism of CHF.Zhenwu decoction can improve the myocardial cell damage,which may be related to its ability to regulate mitochondrial energy metabolism through the PPARα/ASCL1 signaling pathway.This result was verified by Western blot and RT-qPCR experiments.