H2S对大鼠心肌肥大与miRNA-133a和Ca2+/CaN/NFATc4信号通路的影响

doi:10.12047/j.cjap.5492.2018.009

中国应用生理学杂志 ›› 2018, Vol. 34 ›› Issue (1): 29-34.doi: 10.12047/j.cjap.5492.2018.009

H₂S对大鼠心肌肥大与miRNA-133a和Ca²⁺/CaN/NFATc4信号通路的影响

吴扬, 郭媛媛, 张元媛, 张宜

南通大学航海医学研究所, 江苏南通 226019

收稿日期:2016-09-18 修回日期:2017-06-20 出版日期:2018-01-28 发布日期:2018-06-19
通讯作者: 吴扬,Tel:13906292310;E-mail:wy@ntu.edu.cn E-mail:wy@ntu.edu.cn
基金资助:
吴扬,Tel:13906292310;E-mail:wy@ntu.edu.cn

Effects of hydrogen sulfide (H₂S) on cardiac hypertrophy and miRNA-133a-mediated Ca²⁺/calcineurin/NFATc4 signal pathway in rats

WU Yang, GUO Yuan-yuan, ZHANG Yuan-yuan, ZHANG Yi

Institute of Navigation Medicine, Nantong University, Nantong 226019, China

Received:2016-09-18 Revised:2017-06-20 Online:2018-01-28 Published:2018-06-19
Contact: 吴扬,Tel:13906292310;E-mail:wy@ntu.edu.cn E-mail:wy@ntu.edu.cn
Supported by:
吴扬,Tel:13906292310;E-mail:wy@ntu.edu.cn

摘要/Abstract

摘要： 目的：研究硫化氢（H₂S）对心肌细胞肥大的负性调控作用与miRNA-133a介导Ca²⁺/CaN/NFATc4信号通路的关系。方法：异丙肾上腺素（ISO）诱导体外培养的大鼠心肌细胞肥大模型；Leica图像分析软件测量心肌细胞表面积；qRT-PCR检测脑钠尿肽（BNP）、β-肌球蛋白重链（β-MHC）、H₂S合酶（CSE）、miRNA-133a和钙调神经磷酸酶（CaN） mRNA表达；Western blot检测CaN、活化T细胞核因子c4（NFATc4）蛋白表达；Elisa方法检测心肌细胞H₂S含量；激光共聚焦显微镜检测心肌细胞钙离子浓度；细胞免疫荧光检测NFATc4核转位变化。结果：①心肌细胞肥大时，CSE/H₂S水平、miRNA-133a mRNA表达均显著下降。应用NaHS预处理，能上调心肌细胞CSE/H₂S水平，增加H₂S含量和miRNA-133a mRNA表达，并明显抑制心肌细胞肥大。②心肌细胞肥大时，细胞内钙离子浓度明显增加，CaN表达和NFATc4胞核蛋白表达增加，NFATc4核转位明显增强；应用NaHS预处理能明显抑制ISO诱导的上述效应。③应用antagomir-133a能逆转H₂S抑制心肌细胞肥大的作用，使心肌细胞内钙离子浓度、CaN表达和NFATc4胞核蛋白表达增加，NFATc4核转位增强。结论：H₂S通过负性调控作用抑制心肌细胞肥大，该作用可能与H₂S上调miRNA-133a的表达，抑制其下游的Ca²⁺/CaN/NFATc4信号通路的激活有关。

关键词: H₂S, miRNA-133a, Ca²⁺/CaN/NFATc4通路, 心肌细胞肥大, 大鼠

Abstract: Objective: To investigate the effects of hydrogen sulfide (H₂S) on the negatively regulation of cardiomyocyte hypertrophy and the relationship between the effect of H₂S with miRNA-133a-mediated Ca²⁺/calcineurin/NFATc4 signal pathway.Methods: Cardiomyocyte hypertrophy was induced by isoproterenol (ISO). The cell surface area was measured by image analysis system (Leica). The expression of brain natriuretic peptide(BNP), β-myosin heavy chain(β-MHC), cystathionase (CSE), miRNA-133a, calcineurin (CaN) were detected by qRT-PCR. The protein expressions of CaN、nuclear factors of activated T cells (NFATc4) were detected by Western blot. The concentration of H₂S in the cardiomyocyte was detected by Elisa. The concentration of intracellular calcium was measured by calcium imaging using confocal microscope. The nuclear translocation of NFATc4 was checked by immuno-fluorescence cell staining technique.Results: ①The level of system of CSE/H₂S and expression of miRNA-133a were significantly reduced in cardiomyocyte hypertrophy. Pretreatment with NaHS increased the concentration of H₂S and the expression of miRNA-133a mRNA in cardiomyocytes, and suppressed cardiomyocyte hypertrophy. ②The concentration of intracellular calcium, the expression of CaN and nulear protein NFATc4 were significantly increased, and the nuclear translocation of NFATc4 were obviously enhanced in cardiomyocyte hypertrophy. NaHS pretreatment markedly inhibited these effects of ISO induced cardiomyocyte hypertrophy. ③Application of antagomir-133a reversed the inhibitory effects of NaHS on cardiomyocyte hypertrophy, and increased the influx of intracellular calcium, and elevated the expression of CaN and nuclear protein NFATc4, and enhanced the nuclear translocation of NFATc4.Conclusion: H₂S can negatively regulate cardiomyocyte hypertrophy. The effects might be associated with H₂S increasing expression of miRNA-133a and inhibiting inactivation of Ca²⁺/calcineurin/NFATc4 signal pathway.

Key words: H₂S, miRNA-133a, Ca²⁺/calcineurin/NFATc4 signal pathway, cardiomyocyte hypertrophy, rat

吴扬, 郭媛媛, 张元媛, 张宜. H₂S对大鼠心肌肥大与miRNA-133a和Ca²⁺/CaN/NFATc4信号通路的影响[J]. 中国应用生理学杂志, 2018, 34(1): 29-34.

WU Yang, GUO Yuan-yuan, ZHANG Yuan-yuan, ZHANG Yi. Effects of hydrogen sulfide (H₂S) on cardiac hypertrophy and miRNA-133a-mediated Ca²⁺/calcineurin/NFATc4 signal pathway in rats[J]. CJAP, 2018, 34(1): 29-34.

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H₂S对大鼠心肌肥大与miRNA-133a和Ca²⁺/CaN/NFATc4信号通路的影响

Effects of hydrogen sulfide (H₂S) on cardiac hypertrophy and miRNA-133a-mediated Ca²⁺/calcineurin/NFATc4 signal pathway in rats

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