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
| Autor: | Shuang Zhao, Xuesong Li, Chan Chen, Jin Liu, Guoliang Meng, Zhe Lin, Yuanqing Gao, Lihong Pan, Meng-Lin Chao, Albert Ferro, Hong Jiang, Yi Han, Hongshan Chen, Xin Wang, Qiulun Lu, Hong Wang, Liping Xie, Xin Tang, Chun Wang, Yong Ji, Zhengrong Huang, Feiyue Dai |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Inflammasomes muscle lim protein Muscle Proteins Cardiomegaly 030204 cardiovascular system & hematology Rats Inbred WKY Pyrin domain Mixed Function Oxygenases Pathogenesis Mice 03 medical and health sciences 0302 clinical medicine Rats Inbred SHR Physiology (medical) NLR Family Pyrin Domain-Containing 3 Protein myocardium Animals Humans Medicine 030304 developmental biology Mice Knockout 0303 health sciences Toll-like receptor business.industry Kinase Myocardium NOD-like receptor Inflammasome S-Nitrosylation LIM Domain Proteins Toll-Like Receptor 3 Cell biology Disease Models Animal Toll-like receptor 3 Receptor-Interacting Protein Serine-Threonine Kinases TLR3 s-nitrosylation Cardiology and Cardiovascular Medicine business hypertrophy Signal Transduction medicine.drug |
| Zdroj: | Tang, X, Pan, L, Zhao, S, Dai, F, Chao, M, Jiang, H, Li, X, Lin, Z, Huang, Z, Meng, G, Wang, C, Chen, C, Liu, J, Wang, X, Ferro, A, Wang, H, Chen, H, Gao, Y, Lu, Q, Xie, L, Han, Y & Ji, Y 2020, ' 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 ', Circulation, vol. 141, no. 12, pp. 984-1000 . https://doi.org/10.1161/CIRCULATIONAHA.119.042336 |
| DOI: | 10.1161/CIRCULATIONAHA.119.042336 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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