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| Transforming Growth Factor- Induces the Expression of Extracellular Matrix Molecules in Myxomatous Mitral Valves |
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Arnar Geirsson1, Hussain M. Abbas2, Rahmat Ali1, Richard W. Kim1, Juan A. Sanchez2, Sabet Hashim1, George Tellides1; 1Section of Cardiac Surgery, Yale University, New Haven, CT; 2Department of Surgery, St Mary's Hospital, Waterbury, CT Objective: The histological hallmark of myxomatous mitral valve disease is abundant and disorganized extracellular matrix. The primary etiology for myxomatous degeneration in sporadic cases is unknown. Transforming growth factor (TGF)-β has been implicated in the pathogenesis of myxomatous mitral valves in fibrillin-1 deficient mice where treatment with TGF-β antagonism in-vivo rescues the phenotype. The purpose of this study was to test the hypothesis that TGF-β signaling is activated in human myxomatous mitral valve disease. Methods: Mitral valve tissue (posterior leaflet) was obtained from organ donors, cardiac transplant recipients, and patients undergoing mitral valve repair by an approved institutional protocol. Tissue specimens were paraffin embedded and processed for mRNA. Immunohistochemistry was performed using anti-phosphoSMAD 2/3 antibody. Real-time PCR was performed with for multiple extracellular matrix targets. Tissue cultures were performed in serum free RPMI 1640 with or without TGF-β (12 ng/ml) for 6 hours. Results: Histological examination confirmed abundant and disorganized expression of collagen and elastin. By real-time PCR, mRNA transcripts for collagen-1A1, collagen-1A2, collagen-3A1, collagen-5A1, and elastin were significantly increased in myxomatous valves compared to normal valves. Expression of TGF-β1, -β2, and -β3 as well as TGF-β receptor 1 and 3 were also up-regulated in diseased valves (see figure). The association between increased extracellular matrix molecules and TGF-β ligands and receptors was further investigated using an organ culture system. TGF-β treatment of normal mitral valve tissue resulted in up-regulation of collagen-1A1, collagen-1A2, collagen-3A1, and elastin as well as TGF-β1 and TGF-β3 transcripts. Conversely, treatment with TGF-β neutralizing antibody resulted in down-regulation of collagen-1A2, collagen-3A1, and TGF-β1 transcripts. Immunohistochemistry using phospho-SMAD 2/3 antibodies demonstrated increased nuclear labeling in myxomatous mitral valve tissue when compared to non-diseased mitral valves indicating activation of the TGF-β signaling pathway. Conclusion: These results support a functional role for TGF-β signaling in the pathogenesis of myxomatous degeneration suggesting that agents with anti-TGF-β activity might be of potential benefit in patients with myxomatous mitral valve disease. 
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