Ibrutinib Contributes to Atrial Arrhythmia through the Autophagic Degradation of Connexins by Inhibiting the PI3K-AKT-mTOR Signaling Pathway.
Front Biosci (Landmark Ed)
; 29(5): 201, 2024 May 22.
Article
em En
| MEDLINE
| ID: mdl-38812314
ABSTRACT
BACKGROUND:
Ibrutinib could increase the risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL) patients. However, the precise mechanism underlying ibrutinib-induced AF remains incompletely elucidated.METHODS:
We investigated the proportion of ibrutinib-treated CLL patients with new-onset AF. Optical mapping was conducted to reveal the proarrhythmic effect of ibrutinib on HL-1 cells. Fluorescence staining and western blot were used to compare connexins 43 and 40 expression in ibrutinib-treated and control groups. To identify autophagy phenotypes, we used western blot to detect autophagy-related proteins, transmission electron microscopy to picture autophagosomes, and transfected mCherry-GFP-LC3 virus to label autophagosomes and lysosomes. Hydroxychloroquine as an autophagy inhibitor was administered to rescue ibrutinib-induced Cx43 and Cx40 degradation.RESULTS:
About 2.67% of patients developed atrial arrhythmias after ibrutinib administration. HL-1 cells treated with ibrutinib exhibited diminished conduction velocity and a higher incidence of reentry-like arrhythmias compared to controls. Cx43 and Cx40 expression reduced along with autophagy markers increased in HL-1 cells treated with ibrutinib. Inhibiting autophagy upregulated Cx43 and Cx40.CONCLUSIONS:
The off-target effect of ibrutinib on the PI3K-AKT-mTOR signaling pathway caused connexin degradation and atrial arrhythmia via promoting autophagy. CLINICAL TRIAL REGISTRATION ChiCTR2100046062, https//clin.larvol.com/trial-detail/ChiCTR2100046062.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Piperidinas
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Fibrilação Atrial
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Autofagia
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Adenina
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Transdução de Sinais
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Conexinas
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Conexina 43
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Fosfatidilinositol 3-Quinases
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Proteínas Proto-Oncogênicas c-akt
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Serina-Treonina Quinases TOR
Limite:
Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article