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

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

  • Commun Biol. 2023 Feb 9;6(1):161. doi: 10.1038/s42003-023-04534-6.
Mara Stellato 1,  Matthias Dewenter 2,  Michal Rudnik 1,  Amela Hukara 1,  Çagla Özsoy 3 4,  Florian Renoux 1,  Elena Pachera 1,  Felix Gantenbein 5,  Petra Seebeck 5,  Siim Uhtjaerv 1,  Elena Osto 6,  Daniel Razansky 3 4,  Karin Klingel 7,  Joerg Henes 8,  Oliver Distler 1,  Przemysław Błyszczuk 1 9,  Gabriela Kania 10
Affiliations

Affiliations

  • 1 Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
  • 2 Institute of Experimental Cardiology, University Hospital, Heidelberg, Germany.
  • 3 Institute for Biomedical Engineering and Institute of Pharmacology and Toxicology, Faculty of Medicine, University of Zurich, Zurich, Switzerland.
  • 4 Institute for Biomedical Engineering, Department of Information Technology and Electrical Engineering, ETH Zurich, Zurich, Switzerland.
  • 5 Zurich integrative Rodent Physiology, University of Zurich, Zurich, Switzerland.
  • 6 Institute of Clinical Chemistry, University Hospital Zurich, Zurich, Switzerland.
  • 7 Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tubingen, Tubingen, Germany.
  • 8 Internal Medicine II, Division of Rheumatology, University Hospital Tubingen, Tubingen, Germany.
  • 9 Department of Clinical Immunology, Jagiellonian University Medical College, Krakow, Poland.
  • 10 Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. [email protected].
PMID: 36759717 DOI: 10.1038/s42003-023-04534-6
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.

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