期刊
DEVELOPMENTAL DYNAMICS
卷 241, 期 2, 页码 303-314出版社
WILEY-BLACKWELL
DOI: 10.1002/dvdy.23716
关键词
trabeculation; ventricular noncompaction; versican; fibulin-1; Fbln1; ADAMTS-1; ErbB2; Brg1; Erk1; 2; DPEAAE; cardiomyocyte; knockout
资金
- National Institutes of Health [HL095067, HL085618]
- American Heart Association [AHA0755346U, 10SDG2610168]
- NIH South Carolina Clinical and Translational Research Institute (SCTR)
- South Carolina Clinical and Translational Research Institute (SCTR) [RR029881]
- EPSCoR
- Office Of The Director [903795] Funding Source: National Science Foundation
- Office Of The Director
- EPSCoR [919440] Funding Source: National Science Foundation
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. Developmental Dynamics 241:303314, 2012. (C) 2011 Wiley Periodicals, Inc.
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