Effect of neutrophil elastase inhibitor sivelestat on cardiac fibrosis in HFpEF mice
10.3969/j.issn.1000-4718.2025.01.002
- VernacularTitle:中性粒细胞弹性蛋白酶抑制剂sivelestat对HFpEF小鼠心脏纤维化的作用
- Author:
Jing GAN
1
;
Ke ZHANG
;
Hanlin DU
;
Zhuofeng LIN
;
Zhen WU
Author Information
1. 中山大学附属第三医院心血管内科,广东 广州 510630;广东医科大学心血管代谢病创新中心,广东 东莞 523808
- Publication Type:Journal Article
- Keywords:
neutrophil elastase;
sivelestat;
heart failure with preserved ejection fraction;
cardiac fibrosis
- From:
Chinese Journal of Pathophysiology
2025;41(1):11-18
- CountryChina
- Language:Chinese
-
Abstract:
AIM:To investigate the effects of the neutrophil elastase(NE)inhibitor sivelestat on the pathologi-cal changes of cardiac tissues in mice with heart failure with preserved ejection fraction(HFpEF).METHODS:Eight-week-old C57BL/6J mice were randomly divided into 3 groups:control group(n=5),model group(n=6),and treatment group(n=18).The HFpEF mouse model was established using a combined approach of high-fat diet and NG-nitro-L-argi-nine methyl ester(L-NAME).The mice in treatment group received intraperitoneal injection of sivelestat at doses of 12.5,25 and 50 mg·kg-1·d-1(n=6),while those in control and model groups were injected with the same volume of nor-mal saline.After 12 weeks,small animal ultrasound was employed to assess changes in cardiac function,and the lung weight-to-tibia length(LW/TL)ratio was calculated to evaluate pulmonary edema.An exercise fatigue test was conducted to assess exercise intolerance.Histological evaluations were performed using HE,wheat germ agglutinin,dihydroethidium and Sirius red staining to examine overall heart morphology,cross-sectional area of cardiomyocytes,levels of oxidative stress,and the extent of cardiac fibrosis.The expression of fibrosis-related proteins was analyzed using Western blot.RE-SULTS:Compared with model group,sivelestat at various concentrations significantly improved cardiac diastolic function in HFpEF mice,indicated by an increased E/A ratio and a decreased E/e'ratio(P＜0.05).The LW/TL ratio decreased,alleviating lung congestion and exercise intolerance(P＜0.05).The heart weight-to-tibia length(HW/TL)ratio,overall heart cross-sectional area,and cardiomyocyte cross-sectional area all decreased,indicating attenuation in cardiac hypertro-phy(P＜0.05).Additionally,cardiac fibrosis and reactive oxygen species levels were significantly reduced(P＜0.05).CONCLUSION:Inhibition of NE exerts a protective effect against diastolic dysfunction and cardiac fibrosis induced by HFpEF in mice.
