Suche

Roles and mechanisms of NLRP3 inflammasome related signaling in pathogenesis of Brugada Syndrome

https://doi.org/10.1007/s00392-025-02625-4

Chen Yan (Mannheim)1, Z. Meng (Mannheim)1, X. Lei (Mannheim)1, X. Fan (Mannheim)1, L. Cyganek (Göttingen)2, I. El-Battrawy (Bochum)3, X. Zhou (Mannheim)1, I. Akin (Mannheim)1

1Universitätsklinikum Mannheim GmbH I. Medizinische Klinik Mannheim, Deutschland; 2Universitätsmedizin Göttingen Herzzentrum Göttingen - Stem Cell Unit Göttingen, Deutschland; 3Klinikum der Ruhr-Universität Bochum Medizinische Klinik II, Kardiologie Bochum, Deutschland

 

Background: Fever and inflammation can exacerbate the phenotype of Brugada syndrome (BrS). However, there is still a lack of experimental studies investigating the underlying mechanisms of fever or inflammation. NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome is activated during infections. This study aimed to study the potential roles of NLRP3 inflammasome in the effects of inflammation on the phenotype of BrS.

Method: The human induced pluripotent stem cell (hiPSC) lines were generated from fibroblasts of a BrS patient harboring a mutation (c.3148G>A, p.Ala1050Thr)) in SCN5A, as well as from a healthy donor and a site-corrected (using CRISPR/CAS9) cell line. The hiPSC cell lines were used for the differentiation of cardiomyocytes (hiPSC-CMs). qPCR analysis was conducted to measure the mRNA level of PKC subtype (PKC α, PKC β, and PKC ε) after treatment with LPS or LPS plus MCC950, an NLRP3 inflammasome inhibitor. Arrhythmic events in BrS-hiPSC-CMs and healthy or isogenic control were assessed by calcium transient analysis. Sodium channel currents (INa) were measured by patch clamp. Western Blotting was performed to measure SCN5A expression.

Result: LPS reduced peak INa and increased the number of cells showing arrhythmic events in BrS-hiPSC-CMs but not in healthy donor-hiPSC-CMs, implying that LPS can exacerbate BrS phenotype. In addition, effects of LPS were inhibited by the NLRP3 inflammasome inhibitor MCC950. Arrhythmic-like events in BrS-CM were inhibited by MCC950. NLRP3 activator and IL-18 could mimick INa in BrS-CM. LPS significantly increased the expression level of PKC subtypes including PKC-a, PKC-b and PKC-e in healthy donor-hiPSC-CMs and isogenic cells. Strikingly, the LPS effects on PKC level could be inhibited by MCC950 in healthy-, but not BrS-cells, suggesting an involvement of different signaling in BrS-cells.

Conclusion: The NLRP3 inflammasome may contribute to arrhythmogenesis relating to inflammation in BrS patients by reducing PKC α, PKC β, and PKC ε. The NLRP3 inflammasome may be a potential therapeutic target for BrS.
Diese Seite teilen