Long noncoding RNA lncPostn links TGF-β and p53 signaling pathways to transcriptional regulation of cardiac fibrosis

Abstract

Cardiac fibroblasts are essential for the homeostasis of the extracellular matrix whose remodeling in many cardiovascular diseases leads to fibrosis. Long noncoding RNAs (lncRNAs) are associated with cardiac pathologies, but their functions in cardiac fibroblasts and contributions to cardiac fibrosis remain unclear. Here, we aimed to identify fibroblast-enriched lncRNAs essential in myocardial infarction (MI)-induced fibrosis, and explore the molecular mechanisms responsible for their functions. Global lncRNA profiling was performed in post-MI mouse heart ventricles, TGF-β-treated primary cardiac fibroblasts, and confirmed in published datasets. We identified the cardiac fibroblast-enriched lncPostn, whose expression is stimulated in cardiac fibrosis induced by MI and the extracellular growth factor TGF-β. The promotor of lncPostn contains a functional TGF-β response element and lncPostn knockdown results in suppression of TGF-β-stimulated cardiac fibroblast activation and improved cardiac functions post-MI. LncPostn stabilizes and recruits EP300 to the promoter of the pro-fibrotic periostin and represents a major mechanism for its transcriptional activation. Moreover, both MI and TGF-β enhance lncPostn expression while suppressing the cellular growth gatekeeper p53. TGF-β and p53 knockdown-induced pro-fibrotic gene expression and fibrosis occur mainly through lncPostn and show additive effects. Finally, levels of serum lncPostn are significantly increased in patients' post-acute MI and show a strong correlation with fibrosis markers, revealing a potential biomarker of cardiac fibrosis. Our findings identify the fibroblast-enriched lncPostn as a potent pro-fibrotic factor, providing a transcriptional link between TGF-β and p53 signaling pathways to regulate fibrosis in cardiac fibroblasts.