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

doi:10.1038/s42003-023-04534-6

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.

Authors

Mara Stellato¹, Matthias Dewenter², Michal Rudnik¹, Amela Hukara¹, Çagla Özsoy^{3

4}, Florian Renoux¹, Elena Pachera¹, Felix Gantenbein⁵, Petra Seebeck⁵, Siim Uhtjaerv¹, Elena Osto⁶, Daniel Razansky^{3

4}, Karin Klingel⁷, Joerg Henes⁸, Oliver Distler¹, Przemysław Błyszczuk^{1

9}, Gabriela Kania¹⁰

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. gabriela.kania@uzh.ch.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Arrhythmias, Cardiac / genetics
Cardiomyopathies*
Fibrosis
Humans
Mice
Mice, Transgenic
Transcription Factor AP-1*

Substances

Transcription Factor AP-1
Fosl2 protein, mouse