Department of Regenerative Medicine and Cell biology

Research in Focus

Developmental Basis for Inherited Valvular Heart Disease

Linkage and sequencing studies identified mutations in the filamin-A gene in humans with valvular dystrophy. Although the mechanisms by which filamin-A function in the heart are unknown, these genetic findings define filamin-A as an indispensible regulator of valve structure and function. Investigators in the laboratory of Dr. Chip Norris have found that intracellular serotonin is an important mediator of filamin-A function during cardiac valve development. Serotonin is covalently linked to filamin-A via the activity of transglutaminase (TG2). As a functional consequence of this "serotonylation", valvular fibroblasts exhibit enhanced contractility resulting in matrix compaction. Blocking intracellular transport of serotonin and/or TG2 activity results in loss of serotonin-filamin-A interaction and an abrogation of matrix condensation. Consistent with these findings, genetic loss of filamin-A during cardiac development results in enlarged valve leaflets primarily due to failed matrix compaction and organization. Histology, 3D morphometry and echocardiography analyses demonstrate that this initial defect in matrix organization progresses, over time, to a valvular dystrophy phenotype similar to individuals harboring filamin-A mutations. Thus, these findings illustrate a novel contribution of serotonin, TG2 and filamin-A to cardiac valvular development and suggest a mechanistic basis for the pathogenesis of filamin-A mediated valvulopathy. Additionally these data provide evidence that valvular heart disease can be caused by inborn errors of developmental processes; and result in increased susceptibility to clinically expressed disease as the individual ages. A model of our findings is presented.

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Filamin-A functions as a molecular tether between the actin cytoskeleton and the extracellular environment (via integrin b1). During fetal valve development, intracellular serotonin interacts with filamin-A via a TG2 catalyzed reaction and induces a conformation change in the filamin-A protein. This leads to enhanced force generation and "pulling" on the matrix. This results in a compaction and organization of the extracellular matrix. Defects in this process cause valve enlargement during development, which progress, over time, to clinically relevant deficits in valve structure and function.

posted 9/28/2011

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