Objective To investigate the effect and mechanismof Nobiletin(Nob)on necrotic apoptosis in chronic heart failure(CHF)rats by regulating the receptor interacting protein kinase 1/receptor interacting protein kinase 3/mixed line-age kinase like domain protein(RIP1/RIP3/MLKL)signaling pathway.Methods From September 2022 to March 2023,exper-iment was conducted in Central Laboratory of Southern Medical University.A CHF rat model was established,and 75 suc-cessfully modeled rats were randomly divided into model group(CHF group),low-dose Nob group(Nob-L group,7.5 mg·kg-1·d-1 Nob),mediumdose Nob group(Nob-M group,15 mg·kg-1·d-1 Nob),high-dose Nob group(Nob-H group,30 mg·kg-1·d-1 Nob),and pathway inhibitor Nec-1 group(Nec-1 group,2.45 mg·kg-1·d-1 Nec-1)according to the random number table method,with 15 rats in each group.Another 15 rats were selected as the sham operation group(Sham group),with only the thoracic cavity opened and no ligation performed.Echocardiography was applied to detect and detect left ventricular function.Enzyme linked immunosorbent assay(ELISA)was applied to detect the levels of serum tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β),malondialdehyde(MDA),superoxide dismutase(SOD),and total antioxi-dant capacity(T-AOC).Hematoxylin eosin(HE)and Masson staining were applied to observe the pathological changes and fibrosis of myocardial tissue.The terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling(TUNEL)was applied to observe the apoptosis of myocardial tissue.Western blot was applied to detect RIP1,RIP3,MLKL phospho-rylation levels,and Caspase-8 protein expression.Results Compared with the Sham group,some cells in the myocardial tis-sue of the CHF group were damaged,necrotic,structurally disordered,with myocardial cell swelling,a large number of in-flammatory cell infiltration,and collagen deposition and fibrosis in myocardial tissue increased,Compared with the CHF group,the myocardial fiber arrangement of the Nob-L group,Nob-M group,Nob-H group,and Nec-1 group gradually be-came regular,with myocardial cell swelling,necrosis,and the inflammatory cell infiltration decreased,collagen deposition and fibrosis decreased.Compared with the Sham group,the levels of left ventricular end diastolic diameter(LVEDD),left ventric-ular end systolic diameter(LVESD),IL-1β,TNF-αand MDA,cell apoptosis rate,and the expression of p-RIP1/RIP1,p-RIP3/RIP3,and p-MLKL/MLKL proteins of the CHF group,Nob-L group,Nob-M group,Nob-H group and Nec-1 group were obviously increased(P<0.05),the levels of left ventricular ejection fraction(LVEF),left ventricular axis shortening fraction(FS),SOD,T-AOC,and the expression of Caspase-8 protein of the CHF group,Nob-L group,Nob-M group,Nob-H group and Nec-1 group were obviously reduced(F/P=102.557/<0.001,117.684/<0.001,364.401/<0.001,268.087/<0.001,124.566/<0.001,229.003/<0.001,193.585/<0.001,182.164/<0.001,142.657/<0.001,140.900/<0.001,169.680/<0.001,103.485/<0.001,108.277/<0.001,200.435/<0.001),and the intervention effect of different dosage groups of Nob showed a dose-dependent relationship(P<0.05).Conclusion Nob may alleviate inflammation and oxidative stress by inhibiting the activation of the RIP1/RIP3/MLKL signaling pathway,inhibit necrotic apoptosis in CHF rats,and exert a protective effect on CHF rats.
国家科技期刊平台
NSTL
维普
万方数据
