基于Nrf2/SLC7A11/GPX4信号通路探讨栀子-丹参调控铁死亡减轻心肌梗死大鼠心肌重构的机制OA

Objective:To investigate the effect of Gardeniae Fructus-Salviae Miltiorrhizae Radix et Rhizoma on ferroptosis in the rat model of myocardial infarction and further elucidate its role in myocardial remodeling.Methods:The rat model of myocardial infarction was established by ligation of the left anterior descending coronary artery.The 50 successfully modeled rats were randomly divided into model group,ferroptosis inhibitor group(2 mg·kg-1),enalapril group(2.1 mg·kg-1),and low-and high-dose(4 g·kg-1 and 8 g·kg-1,respectively)Gardeniae Fructus-Salviae Miltiorrhizae Radix et Rhizoma,with 10 rats in each group.The rat model of myocardial infarction was established by ligation of the left anterior descending coronary artery.After 4 weeks of treatment,echocardiography was used to assess the cardiac structure and function.Hematoxylin-eosin(HE)staining and Masson staining were employed to observe pathological morphology and fibrosis of the myocardial tissue.Serum levels of N-terminal pro-B-type natriuretic peptide(NT-proBNP),transforming growth factor-β(TGF-β),and myosin heavy chain-β(MHC-β)were measured by enzyme-linked immunosorbent assay(ELISA).Prussian blue staining was performed to detect myocardial iron deposition.The myocardial mitochondrial structure was observed by transmission electron microscopy.Levels of malondialdehyde(MDA)and glutathione(GSH)in the myocardial tissue were determined by lipid peroxidation assay kits.Immunofluorescence assay was conducted to observe the fluorescence intensity of nuclear factor E2-related factor 2(Nrf2)in the myocardial tissue.Western blot analysis was performed to evaluate the expression levels of proteins in the Nrf2/solute carrier family 7 member 11(SLC7A11)/glutathione peroxidase 4(GPX4)pathway.Results:Compared with the sham group,the model group showed increased left ventricular end-diastolic diameter(LVEDD),left ventricular end-systolic diameter(LVESD),and serum levels of NT-proBNP,TGF-β,and MHC-β(P<0.01),decreased left ventricular ejection fraction(LVEF)and left ventricular fractional shortening(LVFS)(P<0.01),disarrangement of myocardial cells,inflammatory cell infiltration,severe myocardial fibrosis,increased myocardial iron deposition,and irregular mitochondrial morphology with vacuolation.Furthermore,the modeling led to increased MDA(P<0.01),decreased GSH(P<0.01),diminished Nrf2 fluorescence intensity in the myocardial tissue,and downregulated expression levels of Nrf2,SLC7A11,and GPX4(P<0.01).Compared with the model group,Gardeniae Fructus-Salviae Miltiorrhizae Radix et Rhizoma reduced the LVEDD,LVESD,and serum levels of NT-proBNP,TGF-β,and MHC-β(P<0.05,P<0.01),increased the LVEF and LVFS(P<0.05,P<0.01),alleviated pathological changes such as myocardial cell disarrangement,inflammatory cell infiltration,myocardial fibrosis,and iron deposition,lowered the level of MDA(P<0.05,P<0.01),raised the level of GSH(P<0.05,P<0.01),improved the mitochondrial morphology and reduced vacuolation in the myocardial tissue,enhanced Nrf2 fluorescence intensity,and upregulated the expression levels of Nrf2,SLC7A11,and GPX4(P<0.05,P<0.01)in the rat model of myocardial infarction.Conclusion:Gardeniae Fructus-Salviae Miltiorrhizae Radix et Rhizoma alleviates pathological damage and myocardial remodeling in the rat model of myocardial infarction by inhibiting ferroptosis,the mechanism of which is related to the activation of Nrf2/SLC7A11/GPX4 signaling pathway.