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首页> 外文期刊>Circulation: An Official Journal of the American Heart Association >SNO-MLP (S-Nitrosylation of Muscle LIM Protein) Facilitates Myocardial Hypertrophy Through TLR3 (Toll-Like Receptor 3)–Mediated RIP3 (Receptor-Interacting Protein Kinase 3) and NLRP3 (NOD-Like Receptor Pyrin Domain Containing 3) Inflammasome Activation
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SNO-MLP (S-Nitrosylation of Muscle LIM Protein) Facilitates Myocardial Hypertrophy Through TLR3 (Toll-Like Receptor 3)–Mediated RIP3 (Receptor-Interacting Protein Kinase 3) and NLRP3 (NOD-Like Receptor Pyrin Domain Containing 3) Inflammasome Activation

机译：通过TLR3（Toll样受体3）介导的RIP3（受体相互作用蛋白激酶3）和NLRP3（含有3个）炎症组的NOR样受体吡林结构域的NLRP3（含有3）炎症组的NLRP3（含有3）炎症组活化的NLRP3（含有3）氨基激活的NLRP3（含有3）活化

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摘要

Supplemental Digital Content is available in the text. Background: S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role of SNO of MLP (muscle LIM protein) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload. Methods: Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. SNO sites were further identified through liquid chromatography–tandem mass spectrometry. Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry and confirmed by coimmunoprecipitation. Recruitment of TLR3 (Toll-like receptor 3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA–transfected neonatal rat cardiomyocytes and in a TLR3 knockout mouse model. Results: SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction. The level of SNO-MLP also increased in angiotensin II– or phenylephrine-treated neonatal rat cardiomyocytes. S-nitrosylated site of MLP at cysteine 79 was identified by liquid chromatography–tandem mass spectrometry and confirmed in neonatal rat cardiomyocytes. Mutation of cysteine 79 significantly reduced hypertrophic growth in angiotensin II– or phenylephrine-treated neonatal rat cardiomyocytes and transverse aortic constriction mice. Reducing SNO-MLP level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, SNO-MLP stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupted this interaction by downregulating TLR3-attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and RIP3 (receptor-interacting protein kinase 3). This interaction in turn induced NLRP3 (nucleotide-binding oligomerization domain–like receptor pyrin domain containing 3) inflammasome activation, thereby promoting the development of myocardial hypertrophy. Conclusions: Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a therapeutic target for myocardial hypertrophy and heart failure.
机译：文本中提供了补充数字内容。背景：S-亚硝基化（SNO），一种原型的氧化还原的后翻译改性，参与心血管疾病的发病机制。本研究的目的是确定MLP（肌肉酸纤维蛋白）在心肌肥大中的角色以及SnO-MLP调节响应压力过载的机制。方法：使用生物素 - 开关方法检查表现出对表现出心肌肥大的患者和动物模型的心肌样本。通过液相色谱 - 串联质谱法进一步鉴定SnO位点。通过亚硝基化位点的突变或S-亚硝基葡萄抑制酶还原酶突变的二氮化物化用于分析SnO-MLP在心肌肥大中的贡献。通过质谱法筛选SnO-MLP的下游效应，并通过CoimMunopectipitation证实。在TLR3小干扰RNA转染的新生大鼠心肌细胞和TLR3敲除小鼠模型中，在心肌肥大中募集TLR3（Toll样受体3）在心肌肥大中进行植物肥大。结果：来自患者的肥厚性心肌的SnO-MLP水平显着高，自发性高血压大鼠和小鼠进行横向性收缩。 SnO-MLP的水平在血管紧张素II-或苯妥治疗的新生大鼠心肌细胞中也增加。通过液相色谱 - 串联质谱法鉴定半胱氨酸79的MLP的S-亚硝基化位点，并在新生大鼠心肌细胞中证实。半胱氨酸79的突变显着降低了血管紧张素II-或苯妥治疗的新生大鼠心肌细胞和横向性收缩小鼠的肥厚生长。通过过表达S-Nitrosogluthuthione还原酶减少SnO-MLP水平大大减毒了心肌肥大。机械地，响应于肥厚刺激，通过下调TLR3减毒的心肌肥大，机械地，SnO-MLP刺激与MLP结合到MLP的结合，并破坏该相互作用。 SnO-MLP还增加了TLR3和RIP3（受体相互作用蛋白激酶3）之间的复杂形成。这种相互作用依次诱导NLRP3（含有3）炎炎症活化的核苷酸结合寡聚域样受体吡林结构域，从而促进心肌肥大的发育。结论：我们的研究结果揭示了SnO-MLP在心肌肥大中的关键作用，并证明了TLR3介导的RIP3和NLRP3炎症剂活化作为下游信号通路，其可以代表心肌肥大和心力衰竭的治疗靶标。

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  • 来源
  • 作者

    Xin Tang; Lihong Pan; Shuang Zhao; Feiyue Dai; Menglin Chao; Hong Jiang; Xuesong Li; Zhe Lin; Zhengrong Huang; Guoliang Meng; Chun Wang; Chan Chen; Jin Liu; Xin Wang; Albert Ferro; Hong Wang; Hongshan Chen; Yuanqing Gao; Qiulun Lu; Liping Xie; Yi Han; Yong Ji;

  • 作者单位

    Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted;

    Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted;

    Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted;

    Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted;

    Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted;

    Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted;

    Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted;

    Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted;

    Department of Cardiology the First Affiliated Hospital of Xiamen University China (Z.H.);

    Nanjing Medical University;

    Department of Geriatrics Nanjing Drum Tower Hospital the Affiliated Hospital of Nanjing;

    Department of Anesthesiology and Translational Neuroscience Center West China Hospital Sichuan;

    Department of Anesthesiology and Translational Neuroscience Center West China Hospital Sichuan;

    Faculty of Biology Medicine and Health the University of Manchester United Kingdom (X.W.);

    Cardiovascular Clinical Pharmacology British Heart Foundation Centre of Research Excellence;

    Department of Pharmacology Lewis Kats School of Medicine Temple University;

    Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted;

    Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted;

    Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted;

    Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted;

    Department of Geriatrics First Affiliated Hospital of Nanjing Medical University China (Y.H.);

    Key Laboratory of Cardiovascular and Cerebrovascular Medicine Key Laboratory of Targeted;

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  • 正文语种 eng
  • 中图分类 心脏、血管（循环系）疾病;
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