Xingbo Xu1, Xiaoying Tan1, Björn Tampe2, Gunsmaa Nyamsuren2, Xiaopeng Liu1, Lars S Maier3, Samuel Sossalla1, Raghu Kalluri4, Michael Zeisberg2, Gerd Hasenfuss5, Elisabeth M Zeisberg6. 1. Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, Germany. 2. Department of Nephrology and Rheumatology, University Medical Center of Göttingen, Georg-August University, Göttingen, Germany. 3. Department of Internal Medicine II, University of Regensburg, Regensburg, Germany. 4. Department of Cancer Biology and the Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA. 5. Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, Germany German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany. 6. Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August University, Robert-Koch-Str. 40, 37075 Göttingen, Germany German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany Elisabeth.Zeisberg@med.uni-goettingen.de.
Abstract
AIMS: Methylation of CpG island promoters is a prototypical epigenetic mechanism to stably control gene expression. The aim of this study was to elucidate the contribution of aberrant promoter DNA methylation in pathological endothelial to mesenchymal transition (EndMT) and subsequent cardiac fibrosis. METHODS AND RESULTS: In human coronary endothelial cells, TGFβ1 causes aberrant methylation of RASAL1 promoter, increased Ras-GTP activity, and EndMT. In end-stage failing vs. non-failing human myocardium, increased fibrosis was associated with significantly increased RASAL1 promoter methylation, decreased RASAL1 expression, increased Ras-GTP activity, and increased expression of markers of EndMT. In mice with pressure overload due to ascending aortic constriction, BMP7 significantly reduced RASAL1 promoter methylation, increased RASAL1 expression, and decreased EndMT markers as well as decreased cardiac fibrosis. The ten eleven translocation (TET) family enzyme TET3, which demethylates through hydroxymethylation, was significantly decreased in fibrotic mouse hearts, restored with BMP7, and BMP7 effects were absent in coronary endothelial cells with siRNA knockdown of TET3. CONCLUSION: Our study provides proof-in-principle evidence that transcriptional suppression of RASAL1 through aberrant promoter methylation contributes to EndMT and ultimately to progression of cardiac fibrosis. Such aberrant methylation can be reversed through Tet3-mediated hydroxymethylation, which can be specifically induced by BMP7. This may reflect a new treatment strategy to stop cardiac fibrosis. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Methylation of CpG island promoters is a prototypical epigenetic mechanism to stably control gene expression. The aim of this study was to elucidate the contribution of aberrant promoter DNA methylation in pathological endothelial to mesenchymal transition (EndMT) and subsequent cardiac fibrosis. METHODS AND RESULTS: In human coronary endothelial cells, TGFβ1 causes aberrant methylation of RASAL1 promoter, increased Ras-GTP activity, and EndMT. In end-stage failing vs. non-failing human myocardium, increased fibrosis was associated with significantly increased RASAL1 promoter methylation, decreased RASAL1 expression, increased Ras-GTP activity, and increased expression of markers of EndMT. In mice with pressure overload due to ascending aortic constriction, BMP7 significantly reduced RASAL1 promoter methylation, increased RASAL1 expression, and decreased EndMT markers as well as decreased cardiac fibrosis. The ten eleven translocation (TET) family enzyme TET3, which demethylates through hydroxymethylation, was significantly decreased in fibrotic mouse hearts, restored with BMP7, and BMP7 effects were absent in coronary endothelial cells with siRNA knockdown of TET3. CONCLUSION: Our study provides proof-in-principle evidence that transcriptional suppression of RASAL1 through aberrant promoter methylation contributes to EndMT and ultimately to progression of cardiac fibrosis. Such aberrant methylation can be reversed through Tet3-mediated hydroxymethylation, which can be specifically induced by BMP7. This may reflect a new treatment strategy to stop cardiac fibrosis. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Jason C Kovacic; Stefanie Dimmeler; Richard P Harvey; Toren Finkel; Elena Aikawa; Guido Krenning; Andrew H Baker Journal: J Am Coll Cardiol Date: 2019-01-22 Impact factor: 24.094