The AP-1 transcription factor Fosl-2 drives cardiac fibrosis and arrhythmias under immunofibrotic conditions
Fibrotic changes in the myocardium and cardiac arrhythmias represent fatal complications in rheumatic disease systemic sclerosis (SSc), however the underlying mechanisms remain elusive. Fos-related antigen-2 (Fosl-2) has been implicated in development of organ fibrosis. Mice overexpressing Fosl-2 (Fosl-2tg) showed interstitial cardiac fibrosis, disorganized connexin43/40 in intercalated discs and deregulated expression of genes controlling conduction system. Fosl-2tg mice 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. To assess the role of inflammation in cardiac fibrosis we used Rag2-/-Fosl-2tg mice lacking T/B cells. These mice showed no myocardial fibrosis and ECG abnormalities. Transcriptomics analysis of cardiac Rag-2-/-Fosl-2wt/Rag2-/-Fosl-2tg/Fosl-2tg fibroblasts revealed that systemic inflammation triggered fibrotic and arrhythmogenic alterations while Fosl-2-overexpression mediated profibrotic signature. In human cardiac fibroblasts FOSL-2-overexpression enhanced myofibroblast signature under proinflammatory or profibrotic stimuli. These results demonstrate that under immunofibrotic conditions activator protein 1 transcription factor component Fosl-2 exaggerates myocardial fibrosis, arrhythmias and aberrant response to stress.