Abstract 11284: Modulation of Transforming Growth Factor-{beta} Signaling and Extracellular Matrix in Myxomatous Mitral Valve Degeneration by Angiotensin II Receptor Blocker Losartan
Background: No specific treatment exists for myxomatous degeneration of the mitral valve, the pathological hallmark of mitral valve prolapse, associated with symptomatic mitral regurgitation, heart failure and death. Transforming growth factor (TGF)-β is known to cause mitral valve degeneration and regurgitation in a mouse model of Marfan syndrome. We investigated the role of TGF-β in sporadic myxomatous mitral valve disease in humans. Methods and results: Mitral valve tissue was obtained from patients undergoing mitral valve operation or from organ recipients and donors. We used standard techniques of immunohistochemistry, immunofluorescence, immunoblotting, FACS and quantitative real-time PCR. Tissue culture techniques and isolated valve interstitial cells (VIC) were used for in-vitro analysis. Excess extracellular matrix components in diseased tissue correlated with TGF-β up-regulation and SMAD2/3 phosphorylation in-vivo and in-vitro. Both TGF-β ligand and signaling mediators co-localized primarily to VIC suggesting autocrine/paracrine activation. In cultured valve tissue, exogenous TGF-β induced collagen and elastin production, whereas serologic neutralization of TGF-β inhibited the disease-driven, pro-fibrotic process. In cultured VIC, pharmacological inhibitors of TGF-β receptor 1 kinase and SMAD3 decreased TGF-β-mediated production of extracellular matrix molecules. Similar effects were seen for angiotensin receptor blockers with described TGF-β inhibitory activity, including losartan. Remarkably, patients with severe mitral regurgitation who had received losartan for several weeks pre-operatively had less TGF-β activity in resected mitral valves than those who had not. Conclusions: TGF-β signaling pathway is up-regulated and plays an essential role in myxomatous mitral valve degeneration where VIC remains the central source of TGF-β ligand. Attenuation of TGF-β signaling by losartan positively affects the pathological processes involved. Successful modulation of clinical complications of mitral valve propapse with a clinically established agent would be of great significance and could provide new mechanistic specific means affecting clinical outcomes of myxomatous mitral valve disease.