Document Detail


Altered versican cleavage in ADAMTS5 deficient mice; a novel etiology of myxomatous valve disease.
MedLine Citation:
PMID:  21749862     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In fetal valve maturation the mechanisms by which the relatively homogeneous proteoglycan-rich extracellular matrix (ECM) of endocardial cushions is replaced by a specialized and stratified ECM found in mature valves are not understood. Therefore, we reasoned that uncovering proteases critical for 'remodeling' the proteoglycan rich (extracellular matrix) ECM may elucidate novel mechanisms of valve development. We have determined that mice deficient in ADAMTS5, (A Disintegrin-like And Metalloprotease domain with ThromboSpondin-type 1 motifs) which we demonstrated is expressed predominantly by valvular endocardium during cardiac valve maturation, exhibited enlarged valves. ADAMTS5 deficient valves displayed a reduction in cleavage of its substrate versican, a critical cardiac proteoglycan. In vivo reduction of versican, in Adamts5(-/-) mice, achieved through Vcan heterozygosity, substantially rescued the valve anomalies. An increase in BMP2 immunolocalization, Sox9 expression and mesenchymal cell proliferation were observed in Adamts5(-/-) valve mesenchyme and correlated with expansion of the spongiosa (proteoglycan-rich) region in Adamts5(-/-) valve cusps. Furthermore, these data suggest that ECM remodeling via ADAMTS5 is required for endocardial to mesenchymal signaling in late fetal valve development. Although adult Adamts5(-/-) mice are viable they do not recover from developmental valve anomalies and have myxomatous cardiac valves with 100% penetrance. Since the accumulation of proteoglycans is a hallmark of myxomatous valve disease, based on these data we hypothesize that a lack of versican cleavage during fetal valve development may be a potential etiology of adult myxomatous valve disease.
Authors:
Loren E Dupuis; Daniel R McCulloch; Jessica D McGarity; Alexandria Bahan; Andy Wessels; Deidra Weber; A Megan Diminich; Courtney M Nelson; Suneel S Apte; Christine B Kern
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-07-01
Journal Detail:
Title:  Developmental biology     Volume:  357     ISSN:  1095-564X     ISO Abbreviation:  Dev. Biol.     Publication Date:  2011 Sep 
Date Detail:
Created Date:  2011-08-15     Completed Date:  2011-11-01     Revised Date:  2014-01-16    
Medline Journal Info:
Nlm Unique ID:  0372762     Medline TA:  Dev Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  152-64     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
ADAM Proteins / genetics*,  metabolism
Animals
Bone Morphogenetic Protein 2 / genetics,  metabolism
Cell Proliferation
Endocardium / metabolism
Gene Expression Regulation, Developmental
Heart / embryology
Heart Valve Diseases / etiology,  genetics
Heart Valves / embryology*,  metabolism
Mesoderm / metabolism
Mice
Mice, Transgenic
Versicans / metabolism*
Grant Support
ID/Acronym/Agency:
AR49930/AR/NIAMS NIH HHS; AR53890/AR/NIAMS NIH HHS; HL084285/HL/NHLBI NIH HHS; P20 RR016434/RR/NCRR NIH HHS; R01 AR049930/AR/NIAMS NIH HHS; R01 AR053890/AR/NIAMS NIH HHS; R01 HL084285/HL/NHLBI NIH HHS; RR016434/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Bone Morphogenetic Protein 2; 126968-45-4/Versicans; EC 3.4.24.-/ADAM Proteins; EC 3.4.24.-/Adamts5 protein, mouse

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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