Volume 39 Issue 2
Feb.  2023
Turn off MathJax
Article Contents
Article Navigation >  Journal of Nanjing University of traditional Chinese Medicine  > 2023  >  39(2): 138-145
ZHANG Meng, WANG Xin-dong. Huangqi-Danshen in the Regulation of ASIC1a/CaMKⅡδ Signaling to Inhibit Cardiomyocytes from Pyroptosis in Acidic Microenvironment[J]. Journal of Nanjing University of traditional Chinese Medicine, 2023, 39(2): 138-145. doi: 10.14148/j.issn.1672-0482.2023.0138
Citation: ZHANG Meng, WANG Xin-dong. Huangqi-Danshen in the Regulation of ASIC1a/CaMKⅡδ Signaling to Inhibit Cardiomyocytes from Pyroptosis in Acidic Microenvironment[J]. Journal of Nanjing University of traditional Chinese Medicine, 2023, 39(2): 138-145. doi: 10.14148/j.issn.1672-0482.2023.0138
shu

Huangqi-Danshen in the Regulation of ASIC1a/CaMKⅡδ Signaling to Inhibit Cardiomyocytes from Pyroptosis in Acidic Microenvironment

doi: 10.14148/j.issn.1672-0482.2023.0138
  • 1.

    The Third School of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China

  • 2.

    Shuguang Hospital, Shanghai University of Chinese Medicine, Shanghai 201203, China

  • Received Date: 2022-08-11
    Available Online: 2023-02-17
    Abstract
  •   OBJECTIVE  To observe the protective effect of Huangqi-Danshen on cardiomyocytes pyroptosis or injury in acidic microenvironment induced by lactic acid and the regulatory mechanism based on the acid-sensitive ion channel 1a (ASIC1a) or calcium/calmodulin-dependent protein kinase Ⅱδ (Ca MKⅡδ) signaling pathway.  METHODS  Lactate was used to stimulate H9C2 cardiomyocytes to establish the cell injury model in the acidic environment of pH 6.5. The rats were divided into the normal control group, model group, Huangqi-Danshen extract (HQ) group, HQ + ASIC agonist Nocistatin group, as well as ASIC inhibitor NS383 positive drug control group. The viability of cardiomyocytes was measured by CCK-8 method. The apoptosis of cardiomyocytes was detected by flow cytometry. Besides, the expression of ASIC1a was detected by immunofluorescence. The mRNA expression of NLRP3, Caspase-1, IL-1β, and GSDMD was analyzed by qPCR. In addition, the protein expression of ASIC1a, CaMKⅡδ, NLRP3, Caspase-1, Cleaved Caspase-1, GSDMD, and GSDME-N was detected by Western blot.  RESULTS  In the acidic environment of pH 6.5, the viability of cardiomyocytes was significantly reduced (P < 0.01), but the apoptosis was significantly increased (P < 0.01). The mRNA expressions of NLRP3, Caspase-1, IL-1β and GSDMD were significantly increased (P < 0.01), and the protein expressions of ASIC1a, CaMKⅡδ, NLRP3, Caspase-1, Cleaved Caspase-1, GSDMD and GSDME-N were also significantly increased (P < 0.01). In addition, we found that HQ (60 μg·mL-1) could significantly promote the viability of cardiomyocytes in acidic microenvironment (P < 0.01), inhibit cardiomyocyte apoptosis (P < 0.01), and down-regulate the mRNA expressions (NLRP3, Caspase-1, IL-1β, GSDMD) combined with protein expressions (ASIC1a, CaMKⅡδ, NLRP3, Caspase-1, Cleaved Caspase-1, GSDMD, GSDME-N) (P < 0.01). Besides, the above effects of HQ can be reversed by ASIC agonist Nocistatin.  CONCLUSION  Huangqi-Danshen can down-regulate ASIC1a/CaMKⅡδ signaling to inhibit NLRP3 inflammasome -mediated cardiomyocyte pyroptosis in acidic microenvironment.

     

    • FullText(HTML)
  • loading
    • References(19)
  • [1]
    SANSBURY BE, DEMARTINO AM, XIE ZZ, et al. Metabolomic analysis of pressure-overloaded and infarcted mouse hearts[J]. Circ Heart Fail, 2014, 7(4): 634-642. doi: 10.1161/CIRCHEARTFAILURE.114.001151
    [2]
    REDD MA, SCHEUER SE, SAEZ NJ, et al. Therapeutic inhibition of acid-sensing ion channel 1a recovers heart function after ischemia-reperfusion injury[J]. Circulation, 2021, 144(12): 947-960. doi: 10.1161/CIRCULATIONAHA.121.054360
    [3]
    TREVANI AS, ANDONEGUI G, GIORDANO M, et al. Extracellular acidification induces human neutrophil activation[J]. J Immunol, 1999, 162(8): 4849-4857. doi: 10.4049/jimmunol.162.8.4849
    [4]
    WALDMANN R, CHAMPIGNY G, BASSILANA F, et al. A proton-gated cation channel involved in acid-sensing[J]. Nature, 1997, 386(6621): 173-177. doi: 10.1038/386173a0
    [5]
    YODER N, YOSHIOKA C, GOUAUX E. Gating mechanisms of acid-sensing ion channels[J]. Nature, 2018, 555(7696): 397-401. doi: 10.1038/nature25782
    [6]
    FRIESE MA, CRANER MJ, ETZENSPERGER R, et al. Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system[J]. Nat Med, 2007, 13(12): 1483-1489. doi: 10.1038/nm1668
    [7]
    LYNAGH T, ROMERO-ROJO JL, LUND C, et al. Molecular basis for allosteric inhibition of acid-sensing ion channel 1a by ibuprofen[J]. J Med Chem, 2017, 60(19): 8192-8200. doi: 10.1021/acs.jmedchem.7b01072
    [8]
    YANG YJ, JIANG K, LIU X, et al. CaMKⅡ in regulation of cell death during myocardial reperfusion injury[J]. Front Mol Biosci, 2021, 8: 668129. doi: 10.3389/fmolb.2021.668129
    [9]
    WILLEFORD A, SUETOMI T, NICKLE A, et al. CaMKⅡδ-mediated inflammatory gene expression and inflammasome activation in cardiomyocytes initiate inflammation and induce fibrosis[J]. JCI Insight, 2018, 3(12): e97054. doi: 10.1172/jci.insight.97054
    [10]
    祁晓霞, 董宇, 单晨啸, 等. 基于UFLC-Q-TOF/MS分析黄芪-丹参药对化学成分研究[J]. 南京中医药大学学报, 2017, 33(1): 93-96, 103. https://www.cnki.com.cn/Article/CJFDTOTAL-NJZY201701022.htm

    QI XX, DONG Y, SHAN CX, et al. Analysis of the main components in herbal pair: Astragali Radix and salviae miltiorrhizae by UFLC-Q-TOF/MS[J]. J Nanjing Univ Tradit Chin Med, 2017, 33(1): 93-96, 103. https://www.cnki.com.cn/Article/CJFDTOTAL-NJZY201701022.htm
    [11]
    王新东, 祁晓霞, 卞勇, 等. 黄芪丹参水煎液抑制ISO诱导的大鼠心肌重构及其下调STIM1, TRPC1, CaN和NFATc3表达的机制[J]. 中国中药杂志, 2017, 42(14): 2738-2743. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGZY201714020.htm

    WANG XD, QI XX, BIAN Y, et al. Huangqi Danshen Decoction attenuates isoproterenol-induced myocardial remodeling via STIM1, TRPC1, CaN and NFATc3 pathways in rats[J]. China J Chin Mater Med, 2017, 42(14): 2738-2743. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGZY201714020.htm
    [12]
    王新东, 卞勇, 祁晓霞. 黄芪丹参水煎液激活AMPK上调自噬抑制ISO诱导的大鼠心肌重构[J]. 中药材, 2017, 40(10): 2433-2436. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYCA201710045.htm

    WANG XD, BIAN Y, QI XX. The decoction of Radix Astragali and Radix Salviae Miltiorrhizae activates AMPK, upregulates autophagy and inhibits ISO-induced myocardial remodeling in rats[J]. J Chin Med Mater, 2017, 40(10): 2433-2436. https://www.cnki.com.cn/Article/CJFDTOTAL-ZYCA201710045.htm
    [13]
    张蒙, 王新东. 黄芪甲苷对缺氧/复氧诱导大鼠心肌细胞能量代谢重编程的影响及机制[J]. 山东医药, 2021, 61(31): 13-16. https://www.cnki.com.cn/Article/CJFDTOTAL-SDYY202131007.htm

    ZHANG M, WANG XD. Effect and mechanism of astragaloside Ⅳ on energy metabolism reprogramming induced by hypoxia/reoxygenation in rat cardiomyocytes[J]. Shandong Med J, 2021, 61(31): 13-16. https://www.cnki.com.cn/Article/CJFDTOTAL-SDYY202131007.htm
    [14]
    TAN Z, XIE N, BANERJEE S, et al. The monocarboxylate transporter 4 is required for glycolytic reprogramming and inflammatory response in macrophages[J]. J Biol Chem, 2015, 290(1): 46-55. doi: 10.1074/jbc.M114.603589
    [15]
    LIN HC, CHEN YJ, WEI YH, et al. Lactic acid fermentation is required for NLRP3 inflammasome activation[J]. Front Immunol, 2021, 12: 630380. doi: 10.3389/fimmu.2021.630380
    [16]
    SUETOMI T, MIYAMOTO S, BROWN JH. Inflammation in nonischemic heart disease: Initiation by cardiomyocyte CaMKⅡ and NLRP3 inflammasome signaling[J]. Am J Physiol Heart Circ Physiol, 2019, 317(5): H877-H890. doi: 10.1152/ajpheart.00223.2019
    [17]
    FENG N, ANDERSON ME. CaMKⅡ is a nodal signal for multiple programmed cell death pathways in heart[J]. J Mol Cell Cardiol, 2017, 103: 102-109. doi: 10.1016/j.yjmcc.2016.12.007
    [18]
    LUCZAK ED, WU YJ, GRANGER JM, et al. Mitochondrial CaMKⅡ causes adverse metabolic reprogramming and dilated cardiomyopathy[J]. Nat Commun, 2020, 11(1): 4416. doi: 10.1038/s41467-020-18165-6
    [19]
    JIANG HL, XING JG, FANG JS, et al. Tilianin protects against ischemia/reperfusion-induced myocardial injury through the inhibition of the Ca2+/calmodulin-dependent protein kinase Ⅱ-dependent apoptotic and inflammatory signaling pathways[J]. Biomed Res Int, 2020, 2020: 5939715.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(4)  / Tables(1)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (183) PDF downloads(21) Cited by()
    Proportional views
    Related

    Copyright © Journal of Nanjing University of traditional Chinese Medicine

    Sponsored by：Nanjing University of traditional Chinese MedicineAddress：No.138 xianlin Avenue, Qixia District, Nanjing cityChina Pos：210023

    Tel：025-85811935Email：xb@njucm.edu.cn

    Supported by: Beijing Renhe Information Technology Co., Ltd.    

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return