Fibulin-1 is required during cardiac ventricular morphogenesis for versican cleavage, suppression of ErbB2 and Erk1/2 activation, and to attenuate trabecular cardiomyocyte proliferation.

Autor: Cooley MA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina 29425-2204, USA., Fresco VM, Dorlon ME, Twal WO, Lee NV, Barth JL, Kern CB, Iruela-Arispe ML, Argraves WS
Jazyk: angličtina
Zdroj: Developmental dynamics : an official publication of the American Association of Anatomists [Dev Dyn] 2012 Feb; Vol. 241 (2), pp. 303-14. Date of Electronic Publication: 2011 Dec 19.
DOI: 10.1002/dvdy.23716
Abstrakt: Background: Trabeculation is an integral component of cardiac ventricular morphogenesis and is dependent on the matrix metalloproteinase, ADAMTS1. A substrate of ADAMTS1 is the proteoglycan versican which is expressed in the developing ventricle and which has been implicated in trabeculation. Fibulin-1 is a versican and ADAMTS1-binding extracellular matrix protein required for ventricular morphogenesis. Here we investigated the involvement of fibulin-1 in ADAMTS1-mediated cleavage of versican in vitro, and the involvement of fibulin-1 in versican cleavage in ventricular morphogenesis.
Results: We show that fibulin-1 is a cofactor for ADAMTS1-dependent in vitro cleavage of versican V1, yielding a 70-kDa amino-terminal fragment. Furthermore, fibulin-1-deficiency in mice was found to cause a significant reduction (>90%) in ventricular levels of the 70-kDa versican V1 cleavage product and a 2-fold increase in trabecular cardiomyocyte proliferation. Decreased versican V1 cleavage and augmented trabecular cardiomyocyte proliferation in fibulin-1 null hearts is accompanied by increased ventricular activation of ErbB2 and Erk1/2. By contrast, versican deficiency was found to lead to decreased cardiomyocyte proliferation and reduced ventricular trabeculation.
Conclusion: We conclude that fibulin-1 regulates versican-dependent events in ventricular morphogenesis by promoting ADAMTS1 cleavage of versican leading to suppression of trabecular cardiomyocyte proliferation mediated by the ErbB2-Map kinase pathway.
(Copyright © 2011 Wiley Periodicals, Inc.)
Databáze: MEDLINE
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