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SHR Neuro Cancer Cardio Lipid Metab Microb

Stellato, M; Dewenter, M; Rudnik, M; Hukara, A; Özsoy, Ç; Renoux, F; Pachera, E; Gantenbein, F; Seebeck, P; Uhtjaerv, S; Osto, E; Razansky, D; Klingel, K; Henes, J; Distler, O; Błyszczuk, P; Kania, G.
The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions.
Commun Biol. 2023; 6(1): 161 Doi: 10.1038/s42003-023-04534-6 [OPEN ACCESS]
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Co-authors Med Uni Graz

Osto Elena

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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-2^tg) represent animal model of SSc. Fosl-2^tg 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-2^tg mice showed impaired HR response. In contrast to Fosl-2^tg, immunodeficient Rag2^-/-Fosl-2^tg 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-2^tg 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.

Find related publications in this database (using NLM MeSH Indexing)

Animals - administration & dosage

Humans - administration & dosage

Mice - administration & dosage

Arrhythmias, Cardiac - genetics

Cardiomyopathies - administration & dosage

Fibrosis - administration & dosage

Mice, Transgenic - administration & dosage

Transcription Factor AP-1 - administration & dosage

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