Cortistatin protects against septic cardiomyopathy by inhibiting cardiomyocyte pyroptosis through the SSTR2-AMPK-NLRP3 pathway.
Int Immunopharmacol
; 134: 112186, 2024 Jun 15.
Article
em En
| MEDLINE
| ID: mdl-38733824
ABSTRACT
BACKGROUND:
Although the pathophysiological mechanism of septic cardiomyopathy has been continuously discovered, it is still a lack of effective treatment method. Cortistatin (CST), a neuroendocrine polypeptide of the somatostatin family, has emerged as a novel cardiovascular-protective peptide, but the specific mechanism has not been elucidated.PURPOSE:
The aim of our study is to explore the role of CST in cardiomyocytes pyroptosis and myocardial injury in sepsis and whether CST inhibits cardiomyocytes pyroptosis through specific binding with somastatin receptor 2 (SSTR2) and activating AMPK/Drp1 signaling pathway. METHODS ANDRESULTS:
In this study, plasma CST levels were significantly high and were negatively correlated with N-terminal pro-B type natriuretic peptide (NT-proBNP), a biomarker for cardiac dysfunction, in patients with sepsis. Exogenous administration of CST significantly improved survival rate and cardiac function in mouse models of sepsis by inhibiting the activation of the NLRP3 inflammasome and pyroptosis of cardiomyocytes (decreased cleavage of caspase-1, IL-1ß and gasdermin D). Pharmacological inhibition and genetic ablation revealed that CST exerted anti-pyroptosis effects by specifically binding to somatostatin receptor subtype 2 (SSTR2), thus activating AMPK and inactivating Drp1 to inhibit mitochondrial fission in cardiomyocytes.CONCLUSIONS:
This study is the first to report that CST attenuates septic cardiomyopathy by inhibiting cardiomyocyte pyroptosis through the SSTR2-AMPK-Drp1-NLRP3 pathway. Importantly, CST specifically binds to SSTR2, which promotes AMPK phosphorylation, inhibits Drp1-mediated mitochondrial fission, and reduces ROS levels, thereby inhibiting NLRP3 inflammasome activation-mediated pyroptosis and alleviating sepsis-induced myocardial injury.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neuropeptídeos
/
Transdução de Sinais
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Receptores de Somatostatina
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Sepse
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Miócitos Cardíacos
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Proteínas Quinases Ativadas por AMP
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Piroptose
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Proteína 3 que Contém Domínio de Pirina da Família NLR
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Camundongos Endogâmicos C57BL
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Cardiomiopatias
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Int Immunopharmacol
Assunto da revista:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China