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

• DOI: 10.1161/circulationaha.119.042336
• Publication Date: 2020-01-06T10:00:31Z
• Authors: 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
• Keywords: Pyrin domain; TLR3

S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim this study was to determine role SNO MLP (muscle LIM protein) myocardial hypertrophy, as well mechanism by which SNO-MLP modulates hypertrophic growth response pressure overload.Myocardial samples from patients and animal models exhibiting hypertrophy were examined for level using biotin-switch methods. sites further identified through liquid chromatography-tandem mass spectrometry. Denitrosylation mutation nitrosylation or overexpression S-nitrosoglutathione reductase used analyze contribution hypertrophy. Downstream effectors screened spectrometry confirmed coimmunoprecipitation. Recruitment TLR3 (Toll-like receptor 3) small interfering RNA-transfected neonatal rat cardiomyocytes knockout mouse model.SNO-MLP significantly higher myocardium spontaneously hypertensive rats mice subjected transverse aortic constriction. also increased angiotensin II- phenylephrine-treated cardiomyocytes. S-nitrosylated site at cysteine 79 Mutation reduced constriction mice. Reducing greatly attenuated Mechanistically, stimulated binding stimuli, disrupted interaction downregulating TLR3-attenuated complex formation between RIP3 (receptor-interacting protein kinase 3). This turn induced NLRP3 (nucleotide-binding oligomerization domain-like pyrin domain containing inflammasome activation, thereby promoting development hypertrophy.Our findings revealed key demonstrated TLR3-mediated activation downstream signaling pathway, may represent therapeutic target heart failure.