益母草活性成分抗心肌肥厚作用及其对Ca2+/CaN/NFATc3/GATA4信号通路的影响

doi:10.3870/j.issn.1672-8009.2026.02.004

医学分子生物学杂志 ›› 2026, Vol. 23 ›› Issue (2): 134-142.doi: 10.3870/j.issn.1672-8009.2026.02.004

益母草活性成分抗心肌肥厚作用及其对Ca²⁺/CaN/NFATc3/GATA4信号通路的影响

吕家顺, 胡伟, 杭燕雯, 毕昌龙, 邱婷婷, 陆益

复旦大学附属闵行医院心血管内科上海市,201100

收稿日期:2025-05-13 出版日期:2026-03-31 发布日期:2026-04-03
通讯作者: 陆益(E-mail:2590075008@qq.com)
基金资助:
上海市闵行区自然研究科学课题(No.2023MHZ102),上海市闵行区公共卫生重点学科建设项目(No.MGWXK2023-12)

Effect of Active Components of Leonurus japonicus on Myocardial Hypertrophy and Ca²⁺/CaN/NFATc3/GATA4 Signaling Pathway

LV Jiashun, HU Wei, HANG Yanwen, BI Changlong, QIU Tingting, LU Yi

Department of Cardiology,Minhang Hospital,Fu Dan University,Shanghai,201100,China

Received:2025-05-13 Online:2026-03-31 Published:2026-04-03
Contact: LU Yi(E-mail:2590075008@qq.com)
Supported by:
Shanghai Natural Science Research in Minhang District(No.2023MHZ102),Shanghai Key Construction Project of Public Health in Minhang District(No.MGWXK2023-12)

摘要/Abstract

摘要： 目的研究益母草活性成分盐酸水苏碱(stachydrine hydrochloride,Sta)抗心肌肥厚作用及其作用机制。方法通过皮下植入缓释渗透泵进行苯肾上腺素(phenylephrine,PE)持续给药14 d,同时12 mg/(kg·d)盐酸水苏碱通过灌胃给药进行干预,小动物超声、HE以及WGA染色观察小鼠心脏结构与功能;计算心脏指数和肥大基因利钠肽(ANP)、脑钠肽(BNP)表达,观察小鼠心肌肥厚程度。乳鼠心肌细胞中PE诱导建立细胞肥大模型,给予5×10^-5mol/L盐酸水苏碱干预48 h,荧光染料标记细胞骨架测量心肌细胞表面积,实时荧光定量PCR(RT-PCR)检测ANP和BNP的表达;离子成像系统记录钙瞬变;酶联免疫吸附法(ELISA)检测钙调蛋白磷酸酶(CaN)活性;免疫荧光检测活化T细胞核因子3(NFATc3)核转位情况;双荧光素酶报告基因检测锌指转录因子(GATA4)转录活性。结果与假手术组比较,PE组心室壁厚度增加(IVSd、LVPWd和LVPWs升高),心脏指数明显增加,HE和WGA染色显示心肌横截面积明显增加,同时伴有肥大基因mRNA表达的升高;Sta干预可以显著降低PE刺激引起的上述指标的增高。细胞实验中,与对照组比较,PE刺激乳鼠心肌细胞48 h可导致细胞表面积增加以及肥大基因表达水平升高,增加钙瞬变幅度引起钙紊乱,导致CaN酶活性过度激活,进而促进NFATc3由细胞质向细胞核的转位;PE刺激H9c2后GATA4的转录活性明显增强;Sta干预可以显著抑制PE诱导引起的以上改变。结论盐酸水苏碱可以通过对Ca²⁺/CaN/NFATc3/GATA4信号通路有效调控改善PE诱导引起的心肌肥厚。

关键词: 盐酸水苏碱, 心肌肥厚, Ca²⁺/CaN/NFATc3/GATA4信号通路

Abstract: Objective To investigate the effect of stachydrine hydrochloride(Sta)on myocardial hypertrophy and the underlying mechanism.Methods C57BL/6 J mice were subjected to subcutaneous implantation of an osmotic pump for continuous administration of phenylephrine(PE)over 14 days and were orally treated with Sta.The small animal ultrasound imaging system was used to detect the cardiac function and structural parameters.HE staining and WGA staining were used to observe the morphological changes of heart and myocardial cells.The mRNA expression of cardiac hypertrophy biomarkers(ANP and BNP)was detected by RT-PCR.Cardiomyocytes were stimulated by PE to mimic hypertrophy,and the cells in the Sta group were treated with 5×10^-5 mol/L Sta for 48 h.Cytoskeleton was labeled with fluorescent dyes to measure cell surface,and the expression of fetal genes was detected by RT-PCR.Moreover,the activity of CaN was tested by ELISA.Calcium transient was detected by ion imaging system.The nuclear translocation of NFATc3 was detected by immunofluorescence.Dual-luciferase reporter assay was conducted to detect the GATA4 transcriptional activity.Results Compared with the sham group,the PE group exhibited an increase in ventricular wall thickness(values of IVSd,LVPWd,and LVPWs were elevated),a significant rise in the cardiac index,and a marked enlargement in the cross-sectional area of cardiomyocytes,accompanied by an upsurge in the mRNA expression levels of hypertrophy-related genes.Sta intervention notably attenuated the increase in these parameters induced by PE stimulation.Cellular experienments showed that cardiomyocytes stimulated with PE demonstrated increases in the cell surface and the expression levels of hypertrophy-related genes,and the increase of calcium transients caused the calcium dysregulation,resulting in an excessive activation of CaN enzyme activity,which in turn promoted the translocation of NFATc3 from the cytoplasm to the nucleus.PE stimulation also significantly enhanced the transcriptional activity of GATA4 in H9c2 cells.Sta intervention significantly inhibited the alterations induced by PE in cardiomyocytes.Conclusion Sta can effectively ameliorate PE-induced myocardial hypertrophy through modulation of the Ca²⁺/CaN/NFATc3/GATA4 signaling pathway.

Key words: stachydrine hydrochloride, cardiac hypertrophy, Ca²⁺/CaN/NFATc3/GATA4 signaling pathway

中图分类号:

R283

吕家顺, 胡伟, 杭燕雯, 毕昌龙, 邱婷婷, 陆益. 益母草活性成分抗心肌肥厚作用及其对Ca²⁺/CaN/NFATc3/GATA4信号通路的影响[J]. 医学分子生物学杂志, 2026, 23(2): 134-142.

LV Jiashun, HU Wei, HANG Yanwen, BI Changlong, QIU Tingting, LU Yi. Effect of Active Components of Leonurus japonicus on Myocardial Hypertrophy and Ca²⁺/CaN/NFATc3/GATA4 Signaling Pathway[J]. Journal of Medical Molecular Biology, 2026, 23(2): 134-142.

参考文献

[1] 国家心血管病中心.中国心血管健康与疾病报告-2023,2023[M].北京:中国协和医科大学出版社,2024.
National Center for Cardiovascular Diseases.Report on Cardiovascular Health and Diseases in China-2023,2023[M].Beijing:China Union Medical College Press,2024.
[2] YANCY C W,JESSUP M,BOZKURT B,et al.2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure:A report of the American college of cardiology/American heart association task force on clinical practice guidelines and the heart failure society of America[J].Circulation,2017,136(6):e137-e161.
[3] NAKAMURA M,SADOSHIMA J.Mechanisms of physiological and pathological cardiac hypertrophy[J].Nat Rev Cardiol,2018,15(7):387-407.
[4] WILD A R,SINNEN B L,DITTMER P J,et al.Synapse-to-nucleus communication through NFAT is mediated by L-type Ca(2+)channel Ca(2+)spike propagation to the soma[J].Cell Rep,2019,26(13):3537-3550.e4.
[5] 柳长华主编.神农本草经——日森立之辑本[M].北京:北京科学技术出版社,2016.
LIU CHANG HUA editor.Shennong Bencao Jing——Japan SEN LI ZHI[M].Beijing:Beijing Science and Technology Publishing Press,2016.
[6] 国家药典委员会.中华人民共和国药典-四部——2020年版[M].北京:中国医药科技出版社,2020.
Chinese Pharmacopoeia Commission.Chinese pharmacopoeia(Ch.P)volume IV——2020 edition[M].Beijing:China Pharmaceutical Science and Technology Press,2020.
[7] ZHANG C,SHAN X L,LIAO Y L,et al.Effects of sta-chydrine on norepinephrine-induced neonatal rat cardiac myocytes hypertrophy and intracellular calcium transients[J].BMC Complement Altern Med,2014,14:474.
[8] LIANG Y,XIA L,LU S,et al.A new mechanism of therapeutic effect of stachydrine on heart failure by inhibiting myocardial ferroptosis[J].Eur J Pharmacol,2023,954:175881.
[9] MARTIN T G,JUARROS M A,LEINWAND L A.Regression of cardiac hypertrophy in health and disease:Mechanisms and therapeutic potential[J].Nat Rev Cardiol,2023,20(5):347-363.
[10] YIN Z,WANG X,ZHANG L,et al.Aspirin attenuates angiotensin II-induced cardiomyocyte hypertrophy by inhibiting the Ca²⁺/calcineurin-NFAT signaling pathway[J].Cardiovasc Ther,2016,34(1):21-29.
[11] LI N,SI B,JU J F,et al.Nicotine induces cardiomyocyte hypertrophy through TRPC3-mediated Ca(2+)/NFAT signalling pathway[J].Can J Cardiol,2016,32(10):1260.e1-1260.e10.
[12] CARDOSO V,CHESNÉ J,RIBEIRO H,et al.Neuronal regulation of type 2 innate lymphoid cells via neuromedin U[J].Nature,2017,549(7671):277-281.
[13] PARRA V,ROTHERMEL B A.Calcineurin signaling in the heart:The importance of time and place[J].J Mol Cell Cardiol,2017,103:121-136.
[14] MOLKENTIN J D.Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs[J].Cardiovasc Res,2004,63(3):467-475.
[15] LI S J,WANG J,MA L,et al.Cooperative autoinhibition and multi-level activation mechanisms of calcineurin[J].Cell Res,2016,26(3):336-349.
[16] SHOU J,JING J,XIE J,et al.Nuclear factor of activated T cells in cancer development and treatment[J].Cancer Lett,2015,361(2):174-184.
[17] SUZUKI H,KATANASAKA Y,SUNAGAWA Y,et al.Tyrosine phosphorylation of RACK1 triggers cardiomyocyte hypertrophy by regulating the interaction between p300 and GATA4[J].Biochim Biophys Acta,2016,1862(9):1544-1557.
[18] XIA Y,MCMILLIN J B,LEWIS A,et al.Electrical stimulation of neonatal cardiac myocytes activates theNFAT3andGATA4pathways and up-regulates the adenylosuccinate synthetase 1 gene[J].J Biol Chem,2000,275(3):1855-1863.
[19] OKA T,MAILLET M,WATT A J,et al.Cardiac-specific deletion of Gata4 reveals its requirement for hypertrophy,compensation,and myocyte viability[J].Circ Res,2006,98(6):837-845.
[20] WANG J,PARADIS P,ARIES A,et al.Convergence of protein kinase C and JAK-STAT signaling on transcription factor GATA-4[J].Mol Cell Biol,2005,25(22):9829-9844.
[21] ZHU X,FANG J,GONG J,et al.Cardiac-specific EPI64C blunts pressure overload-induced cardiac hypertrophy[J].Hypertension,2016,67(5):866-877.

益母草活性成分抗心肌肥厚作用及其对Ca²⁺/CaN/NFATc3/GATA4信号通路的影响

Effect of Active Components of Leonurus japonicus on Myocardial Hypertrophy and Ca²⁺/CaN/NFATc3/GATA4 Signaling Pathway

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