| Objective To observe the effect of Guanxinning Tablets(GXN)on rats with early heart failure(HF)induced by aortic arch stenosis(TAC),and further explore the protective mechanism of GXN on HF model rats from the perspective of brain-gut axis,so as to provide reference for the clinical application of GXN.Methods(1)86 male SPF SD rats were obtained,weighing 220-250 g.After 1 week of adaptive feeding,6 rats underwent sham operation;the remaining 80 rats underwent aortic arch stenosis(TAC).After 4 weeks,the rats after TAC survival were divided into 4 groups according to the left ventricular mass and ejection fraction(EF)as well as body weight,namely the model control group(n=14)and the GXN low dose group(600 mg/kg,n=9),high dose group(1200 mg/kg,n=9)and positive control group(Captopril 12.5 mg/kg,n=9).Each group was received a corresponding drug once a day for 8 weeks.Cardiac ultrasonography was performed every 4 week.The ventricular wall thickness and ejection fraction(EF)were recorded.Serum NT-proBNP,hs-CRP,IL-6,TNF-α,SOD and MDA levels were measured.The pathological structure and collagen fiber deposition of myocardial tissue was observed by H&E and Masson staining,respectively.(2)To observe the effects of GXN on brain-gut axis related indexes,the levels of serum ET-1,NO,MTL,VEGF,CRF and NE were detected by ELISA methods.In addition,the effects of GXN on the structure and function of intestinal flora were observed based on the high-throughput sequencing technology and bioinformatics analysis of 16S gut microbiome.Results(1)Compared with the sham operation group,the survival rate of the model control rats was significantly reduced,and the IVSd,IVSs,LVPWd,LVPWs,LV Mass and mass/body weight,heart weight and coefficient,serum NT-proBNP,hs-CRP,IL-6,TNF-α levels were significantly increased(P<0.05,P<0.01),and BPM,LVET,CO,EF and MDA indexes were also intended to increase,and the activity of SOD was decreased significantly(P<0.05).Histopathological observation showed that myocardial hypertrophy in HF rats(P<0.01),inflammatory infiltration and obvious fibrous tissue hyperplasia,myocardial cells were loose,showing a "net-like" changes,and myocardial fibrosis score was significantly increased(P<0.01).Compared with the model control group,the survival rate of rats with GXN at 1200 mg/kg and 600 mg/kg was increased,while the thickness of the ventricular wall was decreased to some extent.Moreover,IVSs,LVPWd and LVPWs were significantly decreased(P<0.05,P<0.01),and improve the rat heart quality,heart weight and coefficient,myocardial cell size,myocardial tissue inflammatory infiltration and fibrosis,as well as inhibit the increase in NT-proBNP levels in HF rats.In addition,IL-6 level was significantly decreased to the 600 mg/kg GXN group(P<0.05);and in the 1200 mg/kg GXN group,the levels of hs-CRP and TNF-α were significantly reduced(P<0.05)and the serum SOD activity was significantly increased(P<0.05)as well as inhibition of MDA content increase trend(P>0.05).Cardiac coefficient,IVSs,IVSs,LVPWd,LVPWs,NT-proBNP,TNF-α and MDA were also markedly reduced in the positive control group(P<0.05,P<0.01).(2)Compared with the sham operation group,the serum levels of ET-1,ET-1/NO,MTL,VEGF,CRF and NE in the model control group were substantially increased(P<0.05,P<0.01).NO content and intestinal flora diversity were significantly decreased(P<0.05),and the structure and composition of intestinal flora were significantly different from those in the sham operation group.Compared with the model control group,1200 mg/kg and 600 mg/kg GXN as well as the positive control group can significantly reduce serum ET-1 and ET-1/NO ratio(P<0.01),increase the NO content(P<0.05,P<0.01),and each drug intervention group can reduce the levels of MTL,VEGF and CRH,of which 1200 mg/kg GXN group was significantly reduced VEGF levels(P<0.05),while positive control group CRH levels decreased significantly(P<0.01).In addition,GXN intervention can significantly improve the intestinal flora diversity of rats with heart failure,and GXN can improve the composition of intestinal flora.Further LEF Se analysis showed that the possible target genera of GXN were Akkermansia genera,Phascolarctobacterium genera and Oxalobacter genera,and PICRUSt software analysis showed that the effect of GXN on intestinal function in rats with heart failure may be concentrated in non-homologous end-joining,influenza A,carotenoid synthesis,indole alkaloids biosynthesis,betalain biosynthesis,renin-angiotensin system and other biological pathways.Conclusion GXN can effectively alleviate the degree of hypertrophy in rats with heart failure,reduce the level of serum NT-proBNP,inhibit the degree of myocardial remodeling and fibrosis in rats with early heart failure,improve cardiac function,and effectively reduce the inflammatory response and enhancement of antioxidant ability,indicating that GXN has a certain protective effect on early heart failure.GXN can significantly increase NO levels,reduce VEGF,CRF,and NE levels,and significantly improve the intestinal flora diversity of rats with heart failure,and regulate the flora of Akkermansia,Phascolarctobacterium and Oxalobacter,which may affect some biological pathways including carotenoid synthesis,indole alkaloids biosynthesis,betalain biosynthesis,renin-angiotensin system,etc.,and suggest that the mechanism of action of GXN against early heart failure may be related to the regulation of brain gut peptides and intestinal flora. |
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