Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw 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
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- Co-Autor*innen der 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-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.
- 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