达格列净对野百合碱诱导肺动脉高压大鼠的作用及机制研究

Effect and mechanism of dapagliflozin on pulmonary arterial hypertension induced by monocrotaline in rats

目的:探究达格列净(dapagliflozin,DAPA)对野百合碱(monocrotaline,MCT)诱导肺动脉高压(pulmonary arterial hypertension,PAH)大鼠的影响及其作用机制。方法:将30只雄性SD大鼠随机分为对照组(n=10)、肺动脉高压模型组(MCT组,n=10)、达格列净治疗组(DAPA组,n=10),使用MCT(60 mg/kg)单次皮下注射给药构建PAH模型,对照组和MCT组每天给予0.5%羟乙基纤维素钠灌胃,DAPA组给与溶解于0.5%羟乙基纤维素钠的达格列净(1 mg/kg)灌胃。21天后检测大鼠右心室收缩压、右心室肥厚指数;HE染色测量肺小动脉管壁厚度百分比、免疫组化检测肺动脉α-平滑肌肌动蛋白;Western bloting检测肺组织NLRP3、IL-1β和IL-18蛋白表达、ELISA检测血浆IL-1β和IL-18水平。结果:DAPA显著降低了MCT诱导的PAH大鼠右心室收缩压(right ventricular systolic pressure,RVSP)并改善了右心室肥厚、抑制PAH大鼠肺小动脉增厚及降低其肌化程度。此外,DAPA抑制了肺组织中核苷结合域样受体蛋白3(nucleotide-binding domain-like receptor protein 3,NLRP3)炎症小体的激活并下调肺组织和血浆中IL-1β和IL-18的水平。结论:DAPA可以降低MCT诱导PAH大鼠的右心室收缩压、改善右心室肥厚和肺血管重构,并可能与其抑制NLRP3炎症小体激活和下调IL-18与IL-1β表达水平有关。

Objective To investigate the effect of dapagliflozin(DAPA)on monocrotaline(MCT)-induced pulmonary arterial hypertension(PAH)in rats and its mechanism of action.Methods Thirty male SD rats were randomly divided into three groups:(1)Control group,(2)Model group:pulmonary arterial hypertension group,(3)DAPA group:dapagliflozin treatment group.Single subcutaneous injection of MCT(60 mg/kg)was administered to establish the PAH model.The control group and the MCT group were given 0.5%sodium carboxymethyl cellulose by gavage every day,while the DAPA group was given dapagliflozin(1 mg/kg)dissolved in 0.5%sodium carboxymethyl cellulose by gavage.After 21 days,the right ventricular systolic pressure(RVSP)and right ventricular hypertrophy index(RVHI)of rats were measured,the percentage of pulmonary arteriolar wall thickness was measured by HE staining,pulmonary arterial α-smooth muscle actin was detected by immunohistochemistry,NLRP3,IL-1β,and IL-18 protein expression in lung tissue were detected by Western blot,and plasma IL-1β and IL-18 levels were measured by Elisa.Results DAPA significantly reduced RVSP and improved right ventricular hypertrophy in MCT-induced PAH rats,inhibited the thickening of pulmonary arterioles and decreased the degree of muscularization in PAH rats.Furthermore,DAPA inhibited the activation of the NLRP3 inflammasome in lung tissue and down-regulated the levels of IL-1β and IL-18 in lung tissue and plasma.Conclusion DAPA can reduce the RVSP,improve right ventricular hypertrophy and pulmonary vascular remodeling in MCT-induced PAH rats,which may be associated with its inhibition of NLRP3 inflammasome activation and downregulation of IL-18 and IL-1β expression levels.