Key result
Inhibiting muscle LIM protein S-nitrosylation attenuates myocardial hypertrophy by blocking TLR3-mediated RIP3 and NLRP3 activation.
Why the study?
The role of S-nitrosylation of muscle LIM protein in myocardial hypertrophy, and the mechanism modulating hypertrophic growth under pressure overload, was unknown.
S-nitrosylation of MLP at cysteine 79 promotes myocardial hypertrophy via TLR3-mediated RIP3 and NLRP3 inflammasome activation, identifying a potential novel therapeutic target for heart failure.
Answers are grounded in this paper and cite their sources.
No immediate clinical implications for heart failure; leaves open whether SNO-MLP inhibition is a viable target.
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.
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Tang et al. (2020) studied Myocardial hypertrophy. S-nitrosylation of MLP (SNO-MLP) / Cys79 mutation vs. Wild-type MLP / Sham / Non-hypertrophic controls was evaluated on Myocardial hypertrophy (assessed by hypertrophic markers and cell surface area). S-nitrosylation of muscle LIM protein at cysteine 79 facilitates myocardial hypertrophy via TLR3-mediated RIP3 and NLRP3 inflammasome activation, and its inhibition attenuates hypertrophic growth.
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