Abstract 9967: Altered TGF-β Signalling and Myofibroblast-like Cell Differentiation Contribute to Myxomatous Mitral Valve Disease

Upregulated Transforming Growth Factor-beta (TGF-β) signaling has been implicated in the pathogenesis of myxomatous mitral valve disease (MMVD) in both humans and canines. Moreover, it has been postulated that the phenotypic transformation of valve interstitial cells (VICs) in the mitral valve into alpha-smooth muscle actin (α-SMA)-positive myofibroblast-like cells contribute to elevated levels of proteolytic enzymes such as matrix metalloproteinases (MMPs), which subsequently induce pathological remodeling of the extracellular matrix (ECM) in the mitral valve. We hypothesized that, in MMVD, upregulation of TGF-β signaling would induce the transformation of VICs into myofibroblast-like cells, which subsequently express increased levels of MMPs. Computational immunohistochemistry was used to quantify protein expression in mitral valve leaflet tissue from canines affected by MMVD (n=4) and from control canines (n=5). TGF-β and α-SMA expression was significantly increased (p<0.001) in MMVD tissue compared to control tissue. Moreover, a significant positive correlation was found between TGF-β expression and α-SMA expression (p<0.05) across the entire cohort. There were also significant increases in MMP-2 and MMP-9 expression (p<0.05) in MMVD tissue compared to control tissue. No change in MMP-3 expression was detected. These findings are consistent with abnormal TGF-β signaling inducing the differentiation of VICs into α-SMA-positive myofibroblast-like cells. Moreover, the increases in expression of MMP-2 and MMP-9 in MMVD indicate the likely role of these myofibroblast-like cells in mediating pathological remodeling of the ECM throughout the disease process. The paradoxical finding of no change in MMP-3 expression may represent a compensatory mechanism that attempts to limit further degenerative damage to the mitral valve. In conclusion, MMVD is characterized by TGF-β-induced differentiation of VICs into myofibroblast-like cells, which subsequently facilitate ECM degradation via the increased expression of MMPs. This supports the rationale for the use of angiotensin II receptor blockers, capable of attenuating TGF-β signaling, in the treatment of MMVD.