JCVI: Developmental Basis for Filamin-A Associated Myxomatous Mitral Valve Disease.
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Sauls K, de Vlaming A, Harris BS, Williams K, Wessels A, Levine RA, Slaugenhaupt SA, Goodwin RL, Pavone L, Merot J, Schott JJ, Le Tourneau T, Dix T, Jesinkey S, Feng Y, Walsh C, Zhou B, Baldwin S, Markwald RR, Norris RA

Developmental Basis for Filamin-A Associated Myxomatous Mitral Valve Disease.

Cardiovascular research. 2012 Jul 25;

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AIMSWe hypothesized that the structure and function of the mature valves is largely dependent upon how these tissues are built during development and defects in how the valves are built can lead to pathological progression of a disease phenotype. Thus, we sought to uncover potential developmental origins and mechanistic underpinnings causal to myxomatous mitral valve disease. We focus on how filamin-A, a cytoskeletal binding protein with strong links to human myxomatous valve disease, can function as a regulatory interface to control proper mitral valve development.METHODS AND RESULTSFilamin-A deficient mice exhibit abnormally enlarged mitral valves during fetal life, which progresses to a myxomatous phenotype by 2 months of age. Through expression studies, in silico modeling, 3D morphometry, biochemical studies and 3D matrix assays, we demonstrate inception of the valve disease occurs during fetal life and can be attributed, in part, to a deficiency of interstitial cells to efficiently organize the extracellular matrix (ECM). This ECM organization during fetal valve gestation is due, in part, to molecular interactions between filamin-A, serotonin, and the cross-linking enzyme, transglutaminase-2 (TG2). Pharmacological and genetic perturbations that inhibit serotonin-transglutaminase-filamin-A interactions lead to impaired ECM remodeling, and engender progression to a myxomatous valve phenotype.CONCLUSIONSThese findings illustrate a molecular mechanism by which valve interstitial cells, through a serotonin, transglutaminase and filamin-A pathway regulate matrix organization during fetal valve development. Additionally, these data indicate that disrupting key regulatory interactions during valve development can set the stage for the generation of postnatal myxomatous valve disease.