Increased Infiltration of Extra-Cardiac Cells in Myxomatous Valve Disease.

Mutations in the actin-binding gene Filamin-A have been linked to non-syndromic myxomatous valvular dystrophy and associated mitral valve prolapse. Previous studies by our group traced the adult valve defects back to developmental errors in valve interstitial cell-mediated extracellular matrix remodeling during fetal valve gestation. Mice deficient in Filamin-A exhibit enlarged mitral leaflets at E17.5, and subsequent progression to a myxomatous phenotype is observed by two months. For this study, we sought to define mechanisms that contribute to myxomatous degeneration in the adult Filamin-A-deficient mouse. In vivo experiments demonstrate increased infiltration of hematopoietic-derived cells and macrophages in adolescent Filamin-A conditional knockout mice. Concurrent with this infiltration of hematopoietic cells, we show an increase in Erk activity, which localizes to regions of MMP2 expression. Additionally, increases in cell proliferation are observed at two months, when hematopoietic cell engraftment and signaling are pronounced. Similar changes are observed in human myxomatous mitral valve tissue, suggesting that infiltration of hematopoietic-derived cells and/or increased Erk signaling may contribute to myxomatous valvular dystrophy. Consequently, immune cell targeting and/or suppression of pErk activities may represent an effective therapeutic option for mitral valve prolapse patients.