title: Increased Infiltration of Extra-Cardiac Cells in Myxomatous Valve Disease.
abstract: Mutations in the actin-binding geneFilamin-Ahave 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 inFilamin-Aexhibit 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 adultFilamin-A-deficient mouse.In vivoexperiments demonstrate increased infiltration of hematopoietic-derived cells and macrophages in adolescentFilamin-Aconditional 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.
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Children's Research Institute, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Sauls
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Children's Research Institute, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425, USA.
authors.forename: Katelynn
authors.initials: K
authors.lastname: Toomer
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Children's Research Institute, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Williams
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Children's Research Institute, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425, USA.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Children's Research Institute, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425, USA.
authors.forename: Roger R
authors.initials: RR
authors.lastname: Markwald
authors.affiliation: Department of Bioengineering, Clemson University, 200 C Patewood Drive, Greenville, SC 29615, USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Hajdu
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Children's Research Institute, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425, USA.
authors.forename: Russell A
authors.initials: RA
authors.lastname: Norris
keywords: Filamin-A; hematopoietic cells; macrophage; myxomatous valve disease