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

https://doi.org/10.1007/s00392-024-02526-y

Chen Yan (Mannheim)1, Z. Meng (Mannheim)2, X. Lei (Mannheim)1, X. Fan (Mannheim)2, L. Cyganek (Göttingen)3, I. El-Battrawy (Bochum)4, X. Zhou (Mannheim)1, I. Akin (Mannheim)1

1Universitätsklinikum Mannheim GmbH I. Medizinische Klinik Mannheim, Deutschland; 2Universitätsklinikum Mannheim I. Medizinische Klinik Mannheim, Deutschland; 3Universitätsmedizin Göttingen Herzzentrum Göttingen - Stem Cell Unit Göttingen, Deutschland; 4Klinikum der Ruhr-Universität Bochum Medizinische Klinik II, Kardiologie Bochum, Deutschland

 

Background: Fever and inflammation can exacerbate the phenotype of Brugada syndrome (BrS) without experimental studies exploring the underlying mechanisms. 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 differentiated into cardiomyocytes (hiPSC-CMs). LPS was applied to hiPSC-CMs to mimic infection. qPCR, calcium transient, patch clamp and western blotting analyses were performed in the study.

Result: LPS reduced peak INa and increased the number of cells displaying arrhythmic events in BrS-hiPSC-CMs but not in healthy donor-hiPSC-CMs, implying that LPS can exacerbate the BrS phenotype. LPS increased the expression level of PKC subtypes (PKC-a, PKC-b, and PKC-e) in healthy donor-hiPSC-CMs and isogenic cells, but reduced their expression in BrS-hiPSC-CMs, The LPS effects on PKC level could be inhibited by the NLRP3 inflammasome inhibitor (MCC950). Additionally, the arrhythmia-enhancing effect of LPS was also inhibited by MCC950.The LPS inhibitory effect on peak INa could be reversed by PKC inhibitor. PKC ε is involved in LPS effects on peak INa.

Conclusion: Inflammation may trigger arrhythmias in BrS by affecting the NLRP3 inflammasome/PKC signaling. The NLRP3 inflammasome may be a potential therapeutic target for BrS. 

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