1. Developmental basis for filamin-A-associated myxomatous mitral valve disease
- Author
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Christopher A. Walsh, Kimberly Sauls, Richard L. Goodwin, Brett S. Harris, Robert A. Levine, Thierry Le Tourneau, Luigi Michele Pavone, Thomas A. Dix, Annemarieke de Vlaming, Sean Jesinkey, Jean-Jacques Schott, Susan A. Slaugenhaupt, Jean Mérot, Bin Zhou, Roger R. Markwald, Russell A. Norris, Katherine Williams, Andy Wessels, Scott Baldwin, Yuanyi Feng, Sauls, K., de Vlaming, A., Harris, B. S., Williams, K., Wessels, A., Levine, R. A., Slaugenhaupt, S. A., Goodwin, R. L., Pavone, LUIGI MICHELE, Merot, J., Schott, J. J., Le Tourneau, T., Dix, T., Jesinkey, S., Feng, Y., Walsh, C., Zhou, B., Baldwin, S., Markwald, R. R., and Norris, R. A.
- Subjects
Heart Defects, Congenital ,Male ,Serotonin ,Pathology ,medicine.medical_specialty ,Physiology ,Filamins ,Disease ,Tryptophan Hydroxylase ,Matrix (biology) ,Biology ,Filamin ,Extracellular matrix ,Mice ,Contractile Proteins ,GTP-Binding Proteins ,Physiology (medical) ,Mitral valve ,medicine ,Animals ,Mitral valve prolapse ,Protein Glutamine gamma Glutamyltransferase 2 ,Pathological ,Mice, Knockout ,Serotonin Plasma Membrane Transport Proteins ,Mitral Valve Prolapse ,Transglutaminases ,Microfilament Proteins ,Genetic Diseases, X-Linked ,Original Articles ,medicine.disease ,Phenotype ,medicine.anatomical_structure ,Mitral Valve ,Cardiology and Cardiovascular Medicine ,Myxoma - Abstract
Aims We 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 the 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 results Filamin-A-deficient mice exhibit abnormally enlarged mitral valves during foetal life, which progresses to a myxomatous phenotype by 2 months of age. Through expression studies, in silico modelling, 3D morphometry, biochemical studies, and 3D matrix assays, we demonstrate that the inception of the valve disease occurs during foetal life and can be attributed, in part, to a deficiency of interstitial cells to efficiently organize the extracellular matrix (ECM). This ECM organization during foetal 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-TG2-filamin-A interactions lead to impaired ECM remodelling and engender progression to a myxomatous valve phenotype. Conclusions These findings illustrate a molecular mechanism by which valve interstitial cells, through a serotonin, TG, and filamin-A pathway, regulate matrix organization during foetal 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.
- Published
- 2012