Article abstract
Nature Medicine 13, 952 - 961 (2007)
Published online: 29 July 2007 | doi:10.1038/nm1613
Endothelial-to-mesenchymal transition contributes to cardiac fibrosis
Elisabeth M Zeisberg1, Oleg Tarnavski2, Michael Zeisberg1, Adam L Dorfman3, Julie R McMullen4, Erika Gustafsson5, Anil Chandraker6, Xueli Yuan6, William T Pu3, Anita B Roberts7, Eric G Neilson8, Mohamed H Sayegh6, Seigo Izumo2 & Raghu Kalluri1,9,10
Abstract
Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-
1 (TGF-1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis.
- Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, Massachusetts 02215, USA.
- Novartis Institute for Biomedical Research, Cambridge, Massachusetts 02139, USA.
- Department of Cardiology, Children's Hospital, Boston, Massachusetts 02115, USA.
- Cardiovascular Division, Department of Medicine, Department of Cardiology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston, Massachusetts 02215, USA.
- Department of Experimental Pathology, Lund University, 22185 Lund, Sweden.
- Transplantation Research Center, Brigham and Women's Hospital & Children's Hospital, Boston, Massachusetts 02215, USA.
- Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
- Department of Medicine, Vanderbilt University, Nashville, Tennessee 37215, USA.
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA.
- Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts 02215, USA.
Correspondence to: Raghu Kalluri1,9,10 e-mail: rkalluri@bidmc.harvard.edu
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