Effect of sacubactril valsartan sodium combined with atorvastatin calcium on left ventricular remodeling pathway in diabetic patients with heart failure

LI Xiao-xu; YANG Jing; REN Teng-teng

doi:10.3969/j.issn.1672-5301.2025.01.010

Abstract：Objective To investigate the cardioprotective effects of sacubitril valsartan in combination with atovastatin calcium in a rat model of diabetes mellitus(DM)with heart failure(HF)and to preliminarily explore the possible mechanisms of the action.Methods From February 2023 to November 2023,DM model was induced by a one-time intraperitoneal injection of 50 mg/kg streptozotocin,and HF was induced by intraperitoneal injection of 3 mg/kg adriamycin(once a week for 6 weeks)in DM rats.40 rats with successful model construction were randomly divided into the model group,entresto group(10 mg/kg sacubitril valsartan by gavage),meidaxin group(8.4 mg/kg atovastatin calcium by gavage),and combined group(10 mg/kg sacubitril valsartan and 8.4 mg/kg atovastatin calcium gavage),10 in each group;another 10 rats were selected as the control group.Echocardiography was used to assess cardiac function[left ventricular ejection fraction(LVEF),left ventricular fractional shortening(LVFS),left ventricular end-diastolic diameter(LVEDD)and left ventricular end-systolic diameter(LVESD)].The levels of myocardial injury markers[creatine kinase MB(CK-MB)and brain natriuretic peptide(BNP)]in serum were detected.The levels of markers related to oxidative stress[glutathione peroxidase(GSH-Px)and malondialdehyde(MDA)]and inflammation[interleukin-6(IL-6),tumor necrosis factor-α(TNF-α),interleukin-1β(IL-1β)]in myocardial tissue were detected.Hematoxylin eosin staining,TUNEL staining,dihydroethidium(DHE)staining and immunohistochemical analyses were used to determine myocardial tissue pathological injury,cardiomyocyte apoptosis,reactive oxygen species(ROS)levels and positive expression levels of high mobility group protein B1(HMGB1)respectively.Western blotting was used to analyze the expression of HMGB1/Toll-like receptor(TLR)-4/nuclear factor(NF)-κB pathway-related proteins.Results Compared with the control group,LVEF[(34.06±2.08)%vs.(81.35±3.34)%],LVFS[(20.03±1.17)%vs.(52.85±2.54)%]and GSH-Px[(0.84±0.16)μmol/L vs.(3.58±0.96)μmol/L]were significantly decreased in the model group,while LVEDD[(8.97±0.76)mm vs.(5.11±0.57)mm],LVESD[(7.85±0.67)mm vs.(3.14±0.36)mm],CK-MB[(28.26±2.74)ng/ml vs.(9.35±1.16)ng/ml],BNP[(353.76±28.96)pg/ml vs.(220.15±15.75)pg/ml],cross-sectional area of myocardial cells[(526.86±45.26)/μm2 vs.(203.67±23.05)/μm2],proportion of TUNEL positively stained cells[(46.62±2.02)%vs.(1.69±0.43)%],ROS[(6.34±0.13)vs.(1.07±0.09)],MDA[(30.37±2.21)nmol/L vs.(3.69±0.93)nmol/L],IL-6[(34.59±2.25)μ g/g protein vs.(4.37±0.36)μ g/g protein]TNF-α[(63.61±5.33)μ g/g protein vs.(11.19±1.84)μg/g protein],IL-1β[(28.34±3.29)μg/g protein vs.(2.87±0.34)μg/g protein],proportion of HMGB1 positively stained cells[(83.32±1.05)%vs.(26.57±4.37)%],HMGB1 protein[(1.13±0.09)vs.(0.21±0.02)],TLR4 protein[(1.06±0.08)vs.(0.19±0.02)],p-p65/p65 ratio[(0.61±0.05)vs.(0.17±0.02)],and p-IκBα/IκBα ratio[(0.69±0.06)vs.(0.11±0.01)]were significantly increased in the model group(P<0.05).All the above phenomena were improved after treatment with nohindal,metasin or the combination of both,and the combined treatment had a better effect.Conclusion Sacubitril valsartan combined with atovastatin calcium can improve cardiac function,oxidative stress and inflammatory response in DHF rats,and the mechanism may be related to inhibiting the activation of HMGB1/TLR4/NF-κB signaling pathway.