CPB 697 RESEARCH SEMINAR
Kimberly A. Maratea, BA, MS, DVM
Graduate Student in Pathology
Department of Comparative Pathobiology
“Intereference With TGF-β Signaling Using A
Small Molecule TGF-β Receptor I Kinase Inhibitor Causes Valvular Heart
Disease In Sprague-Dawley Rats”
Thursday, March 20, 2008
VPTH
112
3:30
pm
Abstract:
Coordinated signaling of multiple TGF-β superfamily members is known to have a critical role in heart valve development. It has recently been suggested that dysregulation of TGF-β signaling may be a mechanism underlying the pathogenesis of heart valve disease. A novel, rat model of valve disease induced by administration of a small molecule TGF-β type I receptor kinase inhibitor (LY2109761) supports the hypothesis that interference with normal TGF-β signaling causes heart valve disease. Young Sprague-Dawley rats were treated with LY2109761 for 4 consecutive days; tissues were collected on days 2, 5, 14, and 28. Microscopic aortic valve characterized by leaflet thickening, myxomatous degeneration, and accumulation of activated valve interstitial cells were observed in aortic valves of treated rats on days 14 and 28. The cell proliferation index, determined by Ki-67 immunhistochemistry, was increased in treated valves at all of the examined time points. Changes in gene expression were consistent with upregulated TGF-β signaling on days 5 and 14, and increased BMP signaling on day 14. Interestingly, expression of multiple genes associated with extracellular regulation of TGF-β superfamily signaling was significantly decreased on day 2. These findings demonstrate that short-term disruption of TGF-β signaling with LY2109761 predisposes heart valves to pathological remodeling, and suggest that precise regulation of multiple TGF-β superfamily members and downstream effectors is required to maintain postnatal valve architecture.