The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions

Mara Stellato, Matthias Dewenter, Michal Rudnik, Amela Hukara, Çagla Özsoy, Florian Renoux, Elena Pachera, Felix Gantenbein, Petra Seebeck, Siim Uhtjaerv, Elena Osto, Daniel Razansky, Karin Klingel, Joerg Henes, Oliver Distler, Przemysław Błyszczuk, Gabriela Kania

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Fibrotic changes in the myocardium and cardiac arrhythmias represent fatal complications in systemic sclerosis (SSc), however the underlying mechanisms remain elusive. Mice overexpressing transcription factor Fosl-2 (Fosl-2tg) represent animal model of SSc. Fosl-2tg mice showed interstitial cardiac fibrosis, disorganized connexin-43/40 in intercalated discs and deregulated expression of genes controlling conduction system, and developed higher heart rate (HR), prolonged QT intervals, arrhythmias with prevalence of premature ventricular contractions, ventricular tachycardias, II-degree atrio-ventricular blocks and reduced HR variability. Following stimulation with isoproterenol Fosl-2tg mice showed impaired HR response. In contrast to Fosl-2tg, immunodeficient Rag2−/−Fosl-2tg mice were protected from enhanced myocardial fibrosis and ECG abnormalities. Transcriptomics analysis demonstrated that Fosl-2-overexpression was responsible for profibrotic signature of cardiac fibroblasts, whereas inflammatory component in Fosl-2tg mice activated their fibrotic and arrhythmogenic phenotype. In human cardiac fibroblasts FOSL-2-overexpression enhanced myofibroblast signature under proinflammatory or profibrotic stimuli. These results demonstrate that under immunofibrotic conditions transcription factor Fosl-2 exaggerates myocardial fibrosis, arrhythmias and aberrant response to stress.

Original languageEnglish
Article number161
JournalCommunications Biology
Volume6
Issue number1
DOIs
StatePublished - Dec 2023
Externally publishedYes

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