Document Detail


Maladaptive matrix remodeling and regional biomechanical dysfunction in a mouse model of aortic valve disease.
MedLine Citation:
PMID:  22265892     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Aortic valve disease (AVD) occurs in 2.5% of the general population and often requires surgical intervention. Aortic valve malformation (AVM) underlies the majority of cases, suggesting a developmental etiology. Elastin haploinsufficiency results in complex cardiovascular problems, and 20-45% of patients have AVM and/or AVD. Elastin insufficient (Eln+/-) mice demonstrate AVM and latent AVD due to abnormalities in the valve annulus region. The objective of this study was to examine extracellular matrix (ECM) remodeling and biomechanical properties in regional aortic valve tissue and determine the impact of early AVM on late AVD in the Eln+/- mouse model. Aortic valve ECM composition and remodeling from juvenile, adult, and aged stages were evaluated in Eln+/- mice using histology, ELISA, immunohistochemistry and gelatin zymography. Aortic valve tissue biomechanical properties were determined using micropipette aspiration. Cartilage-like nodules were demonstrated within the valve annulus region at all stages identifying a developmental abnormality preceding AVD. Interestingly, maladaptive ECM remodeling was observed in early AVM without AVD and worsened with late AVD, as evidenced by increased MMP-2 and MMP-9 expression and activity, as well as abnormalities in ADAMTS-mediated versican processing. Cleaved versican was increased in the valve annulus region of aged Eln+/- mice, and this abnormality correlated temporally with adverse alterations in valve tissue biomechanical properties and the manifestation of AVD. These findings identify maladaptive ECM remodeling in functional AVM as an early disease process with a progressive natural history, similar to that seen in human AVD, emphasizing the importance of the annulus region in pathogenesis. Combining molecular and engineering approaches provides complementary mechanistic insights that may be informative in the search for new therapeutic targets and durable valve bioprostheses.
Authors:
Varun K Krishnamurthy; Amy M Opoka; Christine B Kern; Farshid Guilak; Daria A Narmoneva; Robert B Hinton
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-01-12
Journal Detail:
Title:  Matrix biology : journal of the International Society for Matrix Biology     Volume:  31     ISSN:  1569-1802     ISO Abbreviation:  Matrix Biol.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-03-06     Completed Date:  2012-06-27     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  9432592     Medline TA:  Matrix Biol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  197-205     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
ADAM Proteins / metabolism
Animals
Aortic Diseases / metabolism,  pathology*
Aortic Valve / abnormalities,  metabolism,  pathology
Biomechanical Phenomena
Disease Models, Animal
Elastin / metabolism
Enzyme Activation
Enzyme-Linked Immunosorbent Assay
Extracellular Matrix / metabolism,  pathology*
Female
Haploinsufficiency
Heart Valve Diseases / metabolism,  pathology*
Immunohistochemistry
Male
Matrix Metalloproteinase 9 / metabolism
Mice
Mice, Inbred C57BL
Structure-Activity Relationship
Tensile Strength
Versicans / metabolism
Grant Support
ID/Acronym/Agency:
AR15768/AR/NIAMS NIH HHS; DK078814/DK/NIDDK NIH HHS; HL085122/HL/NHLBI NIH HHS; K23 HL085122/HL/NHLBI NIH HHS; K23 HL085122-05/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cspg2 protein, rat; 126968-45-4/Versicans; 9007-58-3/Elastin; EC 3.4.24.-/ADAM Proteins; EC 3.4.24.-/Adamts9 protein, mouse; EC 3.4.24.-/Mmp9 protein, mouse; EC 3.4.24.35/Matrix Metalloproteinase 9
Comments/Corrections

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