| First Author | Stellato M | Year | 2023 |
| Journal | Commun Biol | Volume | 6 |
| Issue | 1 | Pages | 161 |
| PubMed ID | 36759717 | Mgi Jnum | J:344603 |
| Mgi Id | MGI:7433335 | Doi | 10.1038/s42003-023-04534-6 |
| Citation | Stellato M, et al. (2023) The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions. Commun Biol 6(1):161 |
| abstractText | 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. |
