Abstract 14958: Role of Gata4 in Reduction of Fibrosis After Myocardial Infarction
Background: A variety of cardio-differentiating transcription factors, including Gata4, Mef2c andTbx5 (GMT) have been shown to reprogram cardiac fibroblasts into induced cardiomyocyte-like cells (iCMs), and improve post-infarct ventricular function in vivo. Reductions in fibrosis observed after reprogramming factor administration seem to far exceed the extent of iCM generation. We therefore sought to identify potential GMT-mediated anti-fibrotic molecular pathways.
Methods: Adult rat cardiac fibroblasts (RCF) were infected with lentivirus encoding GMT or a null vector, and gene and protein expression assays performed to identify relevant anti-fibrotic targets of these factors.
Results: GMT administration to RCFs in vitro significantly downregulated expression of Snail, and the pro-fibrotic factors, CTGF, Collagen1a1, and Fibronectin. Of the three reprogramming factors, Gata4 was shown to be the one responsible for the downregulation of Snail (mRNA expression fold change relative to GFP, Gata4: 0.5 ± 0.1, Mef2c: 1.3 ± 0.6, Tbx5: 0.8 ± 0.4, GMT: 0.6 ± 0.1, p<0.05) and other pro-fibrotic factors. ChIP qPCR identified Gata4 binding sites in the Snail promoter. Furthermore, Gata4 binding sites at the Snail promoter were co-occupied by HDAC2 while H3K27ac binding was decreased at the same sites when compared to non-Gata4 binding site, suggesting that Gata4 represses the transcription of Snail epigenetically through its interaction with HDAC2.
Conclusion: Gata4 may be a primary cardiac cellular reprogramming factor responsible for reducing post-infarct fibrosis, and we have traced this potentially to Gata4 mediated Snail suppression. Further exploration of primary anti-fibrotic effects of cardiac cellular reprogramming strategies appears warranted.
Author Disclosures: M. Mathison: None. V. Singh: None. D. Sanagasetti: None. L. Yang: None. V. Patel: None. J. Yang: None. T. Rosengart: None.
- © 2016 by American Heart Association, Inc.