Document Detail


Loss of Krox20 results in aortic valve regurgitation and impaired transcriptional activation of fibrillar collagen genes.
MedLine Citation:
PMID:  25344368     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
AIMS: Heart valve maturation is achieved by organization of extracellular matrix and distribution of valvular interstitial cells. However, the factors that regulate matrix components required for valvular structure and function are unknown. Based on the discovery of its specific expression in cardiac valves, we aimed to uncover the role of Krox20 (Egr-2) during valve development and disease.
METHODS AND RESULTS: Using series of mouse genetic tools we demonstrated that loss of function of Krox20 caused significant hyperplasia of the semilunar valves, while atrioventricular valves appeared normal. This defect was associated with an increase of valvular interstitial cell number and extracellular matrix volume. Echo-Doppler analysis revealed that adult mutant mice had aortic insufficiency. Defective aortic valves in Krox20(-/-) mice had features of human aortic valve disease, including excess of proteoglycan deposition and reduction of collagen fibers. Furthermore, examination of diseased human aortic valves revealed decreased expression of KROX20. To identify downstream targets of Krox20, we examined expression of fibrillar collagens in the aortic valve leaflets at different stages in the mouse. We found significant downregulation of Col1a1, Col1a2 and Col3a1 in the semilunar valves of Krox20 mutant mice. Utilizing in vitro and in vivo experiments we demonstrated that Col1a1 and Col3a1 are direct targets of Krox20 activation in interstitial cells of the aortic valve.
CONCLUSION: This study identifies a previously unknown function of Krox20 during heart valve development. These results indicate that Krox20-mediated activation of fibrillar Col1a1 and Col3a1 genes is crucial to avoid postnatal degeneration of the aortic valve leaflets.
Authors:
Gaëlle Odelin; Emilie Faure; Frank Kober; Corinne Maurel-Zaffran; Alexis Théron; Fanny Coulpier; Benjamin Guillet; Monique Bernard; Jean-François Avierinos; Patrick Charnay; Piotr Topilko; Stéphane Zaffran
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-10-24
Journal Detail:
Title:  Cardiovascular research     Volume:  -     ISSN:  1755-3245     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2014 Oct 
Date Detail:
Created Date:  2014-10-25     Completed Date:  -     Revised Date:  2014-10-26    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.
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