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

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摘要 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。

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	孙倩
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	颜素岚
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	邹琼超

关键词 ：达格列净, 肺动脉高压, 肺血管重构, 右心室肥厚

Abstract：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.

Key words： dapagliflozin pulmonary artertension hypertension pulmonary vascular remodeling right ventricular hypertrophy

收稿日期: 2023-09-04

中图分类号:

R363

基金资助:湖南省卫生健康委科研计划项目“SGLT2抑制剂通过抑制NLRP3炎性小体活化改善肺血管重构的研究”（202103012120）

通讯作者: 邹琼超,E-mail：zouqiongchao@126.com

引用本文:

孙倩, 王健, 刘芬, 颜素岚, 彭建强, 邹琼超. 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[J]. 湖南师范大学学报(医学版), 2023, 20(6): 14-19. SUN Qian, WANG Jian, LIU Fen, YAN Sulan, PENG Jianqiang, ZOU Qiongchao. Effect and mechanism of dapagliflozin on pulmonary arterial hypertension induced by monocrotaline in rats. HuNan ShiFan DaXue XueBao(YiXueBan), 2023, 20(6): 14-19.

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http://yxb.hunnu.edu.cn/CN/ 或 http://yxb.hunnu.edu.cn/CN/Y2023/V20/I6/14

[1] HASSOUN PM.Pulmonary Arterial Hypertension[J]. N Engl J Med, 2021, 385(25): 2361-2376.
[2] BOUCHERAT O, AGRAWAL V, LAWRIE A, et al.The Latest in Animal Models of Pulmonary Hypertension and Right Ventricular Failure[J]. Circulation research, 2022, 130(9): 1466-1486.
[3] LEOPOLD JA.Initial Triple Pharmacotherapy in Pulmonary Arterial Hypertension: Is More Necessarily Better?[J]. J Am Coll Cardiol, 2021, 78(14): 1404-1406.
[4] SITBON O, SATTLER C, BERTOLETTI L, et al.Initial dual oral combination therapy in pulmonary arterial hypertension[J]. Eur Respir J, 2016, 47(6): 1727-1736.
[5] FARBER HW, MILLER DP, POMS AD, et al.Five-Year outcomes of patients enrolled in the REVEAL Registry[J]. Chest, 2015, 148(4): 1043-1054.
[6] XU B, LI S, KANG B, et al.The current role of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes mellitus management[J]. Cardiovasc Diabetol, 2022, 21(1): 83.
[7] MCMURRAY JJV, SOLOMON SD, INZUCCHI SE, et al.Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction[J]. N Engl J Med, 2019, 381(21): 1995-2008.
[8] PETRIE MC, VERMA S, DOCHERTY KF, et al.Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes[J]. Jama, 2020, 323(14): 1353-1368.
[9] CHOWDHURY B, LUU AZ, LUU VZ, et al.The SGLT2 inhibitor empagliflozin reduces mortality and prevents progression in experimental pulmonary hypertension[J]. Biochem Biophys Res Commun, 2020, 524(1): 50-56.
[10] CERO FT, HILLESTAD V, SJAASTAD I, et al.Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice[J]. Am J Physiol Lung Cell Mol Physiol, 2015, 309(4): L378-L387.
[11] UDJUS C, CERO FT, HALVORSEN B, et al.Caspase-1 induces smooth muscle cell growth in hypoxia-induced pulmonary hypertension[J]. Am J Physiol Lung Cell Mol Physiol.2019, 316(6): L999-L1012.
[12] PARPALEIX A, AMSELLEM V, HOUSSAINI A, et al.Role of interleukin-1 receptor 1/MyD88 signalling in the development and progression of pulmonary hypertension[J]. Eur Respir J, 2016, 48(2): 470-483.
[13] SOON E, HOLMES AM, TREACY CM, et al.Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension[J]. Circulation, 2010, 122(9): 920-927.
[14] TRANKLE CR, CANADA JM, KADARIYA D, et al.IL-1 Blockade Reduces Inflammation in Pulmonary Arterial Hypertension and Right Ventricular Failure: A Single-Arm, Open-Label, Phase IB/II Pilot Study[J]. Am J Respir Crit Care Med, 2019, 199(3): 381-384.
[15] LOPASCHUK GD, VERMA S.Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2(SGLT2) Inhibitors: A State-of-the-Art Review[J]. JACC Basic Transl Sci, 2020, 5(6): 632-644.
[16] UGUSMAN A, KUMAR J, Aminuddin A.Endothelial function and dysfunction: Impact of sodium-glucose cotransporter 2 inhibitors[J]. Pharmacol Ther, 2021, 224: 107832.
[17] BYRNE NJ, MATSUMURA N, MAAYAH ZH, et al.Empagliflozin Blunts Worsening Cardiac Dysfunction Associated With Reduced NLRP3(Nucleotide-Binding Domain-Like Receptor Protein 3) Inflammasome Activation in Heart Failure[J]. Circ Heart Fail, 2020, 13(1): e006277.
[18] VAN DE VEERDONK MC, KIND T, MARCUS JT, et al. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy[J]. J Am Coll Cardiol, 2011, 58(24): 2511-2519.
[19] HILL NS, GILLESPIE MN, MCMURTRY IF.Fifty Years of Monocrotaline-Induced Pulmonary Hypertension: What Has It Meant to the Field?[J]. Chest, 2017, 152(6): 1106-1108.
[20] DORFMÜLLER P, PERROS F, BALABANIAN K, et al. Inflammation in pulmonary arterial hypertension[J]. Eur Respir J, 2003, 22(2): 358-363.
[21] LI H, ZHANG Y, WANG S, et al.Dapagliflozin has No Protective Effect on Experimental Pulmonary Arterial Hypertension and Pulmonary Trunk Banding Rat Models[J]. Front Pharmacol, 2021, 12: 756226.
[22] THOMPSON AAR, LAWRIE A.Targeting Vascular Remodeling to Treat Pulmonary Arterial Hypertension[J]. Trends Mol Med, 2017, 23(1): 31-45.
[23] WANG RR, YUAN TY, WANG JM, et al.Immunity and inflammation in pulmonary arterial hypertension: From pathophysiology mechanisms to treatment perspective[J]. Pharmacol Res, 2022, 180: 106238.
[24] LIU Z, MA X, ILYAS I, et al.Impact of sodium glucose cotransporter 2(SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics[J]. Theranostics, 2021, 11(9): 4502-4515.
[25] SUN XQ, ABBATE A, BOGAARD HJ.Role of cardiac inflammation in right ventricular failure[J]. Cardiovasc Res, 2017, 113(12): 1441-1452.
[26] TANG B, CHEN GX, LIANG MY, et al.Ellagic acid prevents monocrotaline-induced pulmonary artery hypertension via inhibiting NLRP3 inflammasome activation in rats[J]. Int J Cardiol, 2015, 180: 134-141.
[27] KIM SR, LEE SG, KIM SH, et al.SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease[J]. Nat Commun, 2020, 11(1): 2127.
[28] QUAGLIARIELLO V, DE LAURENTIIS M, REA D, et al.The SGLT-2 inhibitor empagliflozin improves myocardial strain, reduces cardiac fibrosis and pro-inflammatory cytokines in non-diabetic mice treated with doxorubicin[J]. Cardiovasc Diabetol, 2021, 20(1): 150.
[29] YARIBEYGI H, KATSIKI N, BUTLER AE, et al.Effects of antidiabetic drugs on NLRP3 inflammasome activity, with a focus on diabetic kidneys[J]. Drug Discov Today, 2019, 24(1): 256-262.