The effect of transforming growth factor-beta type I receptor kinase inhibition on the heart valves of Sprague-Dawley rats

Altered transforming growth factor beta (TGF-β) signaling has been implicated in the pathogenesis of heart valve diseases of diverse etiologies. However, the role of TGF-β in the initiation and progression of valve disease remains poorly understood. A rat model of valvulopathy induced by oral administration of the small molecule TGF-β type I receptor (ALK5) kinase inhibitor LY2109761 was used to investigate the role of TGF-β signaling in heart valve disease. Rats treated with LY2109761 daily for either 4 or 14 consecutive days developed valvulopathy characterized by leaflet thickening, increased cell proliferation, accumulation of myxomatous matrix, and valve interstitial cell (VIC) activation by day 14. In rats treated with LY2109761 for 4 days, mRNA from heart valves had increased mRNA expression of PAI-1 on days 5 and 14, suggesting that TGF-β signaling was activated following termination of LY2109761 treatment. Although cell proliferation, VIC activation, and expression of TGF-β-responsive genes returned to baseline levels by day 28, the valve lesions persisted, indicating they may be irreversible. In contrast, the valves from rats treated with LY2109761 for 14 days had decreased mRNA expression of PAI-1 and decreased nuclear Smad2 phosphorylation, both indicators of decreased TGF-β signaling. These findings support the hypothesis that TGF-β is a key mediator of heart valve disease, and suggest that PAI-1 may be the primary downstream mediator of pathological remodeling in affected valves. Further investigation will be necessary to better understand the mechanism of LY2109761-induced valvulopathy and determine if the contradiction in mRNA expression data is associated with dysregulation of TGF-β signaling or related to the pharmacokinetics of LY2109761