Cardiac reprogramming factor Gata4 reduces postinfarct cardiac fibrosis through direct repression of the profibrotic mediator snail

The administration of a variety of reprogramming factor cocktails has now been shown to reprogram cardiac fibroblasts into induced cardiomyocyte-like cells. However, reductions in ventricular fibrosis observed after reprogramming factor administration seem to far exceed the extent of induced cardiom...

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Bibliographic Details
Published in:The Journal of thoracic and cardiovascular surgery 2017-11, Vol.154 (5), p.1601-1610.e3
Main Authors: Mathison, Megumi, Singh, Vivek P., Sanagasetti, Deepthi, Yang, Lina, Pinnamaneni, Jaya Pratap, Yang, Jianchang, Rosengart, Todd K.
Format: Article
Language:English
Subjects:
Animals
cardiac reprogramming
Cellular Reprogramming - genetics
Cellular Reprogramming Techniques
Collagen Type I - analysis
Connective Tissue Growth Factor - analysis
Down-Regulation
Fibroblasts - physiology
Fibronectins - analysis
fibrosis
Fibrosis - metabolism
Fibrosis - prevention & control
Gata4
GATA4 Transcription Factor - metabolism
GATA4 Transcription Factor - pharmacology
Genetic Vectors
Lentivirus
MEF2 Transcription Factors - metabolism
MEF2 Transcription Factors - pharmacology
Myocytes, Cardiac - physiology
Rats
Signal Transduction
Snail
Snail Family Transcription Factors
T-Box Domain Proteins - metabolism
T-Box Domain Proteins - pharmacokinetics
Zinc Fingers
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Summary:The administration of a variety of reprogramming factor cocktails has now been shown to reprogram cardiac fibroblasts into induced cardiomyocyte-like cells. However, reductions in ventricular fibrosis observed after reprogramming factor administration seem to far exceed the extent of induced cardiomyocyte-like cell generation in vivo. We investigated whether reprogramming factor administration might primarily play a role in activating antifibrotic molecular pathways. Adult rat cardiac fibroblasts were infected with lentivirus encoding the transcription factors Gata4, Mef2c, or Tbx5, all 3 vectors, or a green fluorescent protein control vector. Gene and protein expression assays were performed to identify relevant antifibrotic targets of these factors. The antifibrotic effects of these factors were then investigated in a rat coronary ligation model. Gata4, Mef2c, or Tbx5 administration to rat cardiac fibroblasts in vitro significantly downregulated expression of Snail and the profibrotic factors connective tissue growth factor, collagen1a1, and fibronectin. Of these factors, Gata4 was shown to be the one responsible for the downregulation of the profibrotic factors and Snail (mRNA expression fold change relative to green fluorescent protein for Snail, Gata4: 0.5 ± 0.3, Mef2c: 1.3 ± 1.0, Tbx5: 0.9 ± 0.5, Gata4, Mef2c, or Tbx5: 0.6 ± 0.2, P 
ISSN:0022-5223
1097-685X
DOI:10.1016/j.jtcvs.2017.06.035