| Elastin haploinsufficiency results in progressive aortic valve malformation and latent valve disease in a mouse model. | |
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MedLine Citation:
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PMID: 20576933 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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RATIONALE: Elastin is a ubiquitous extracellular matrix protein that is highly organized in heart valves and arteries. Because elastic fiber abnormalities are a central feature of degenerative valve disease, we hypothesized that elastin-insufficient mice would manifest viable heart valve disease. OBJECTIVE: To analyze valve structure and function in elastin-insufficient mice (Eln(+/-)) at neonatal, juvenile, adult, and aged adult stages. METHODS AND RESULTS: At birth, histochemical analysis demonstrated normal extracellular matrix organization in contrast to the aorta. However, at juvenile and adult stages, thin elongated valves with extracellular matrix disorganization, including elastin fragment infiltration of the annulus, were observed. The valve phenotype worsened by the aged adult stage with overgrowth and proteoglycan replacement of the valve annulus. The progressive nature of elastin insufficiency was also shown by aortic mechanical testing that demonstrated incrementally abnormal tensile stiffness from juvenile to adult stages. Eln(+/-) mice demonstrated increased valve interstitial cell proliferation at the neonatal stage and varied valve interstitial cell activation at early and late stages. Gene expression profile analysis identified decreased transforming growth factor-beta-mediated fibrogenesis signaling in Eln(+/-) valve tissue. Juvenile Eln(+/-) mice demonstrated normal valve function, but progressive valve disease (predominantly aortic regurgitation) was identified in 17% of adult and 70% of aged adult Eln(+/-) mice by echocardiography. CONCLUSIONS: These results identify the Eln(+/-) mouse as a model of latent aortic valve disease and establish a role for elastin dysregulation in valve pathogenesis. |
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Authors:
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Robert B Hinton; Jennifer Adelman-Brown; Sandra Witt; Varun K Krishnamurthy; Hanna Osinska; Bhuvaneswari Sakthivel; Jeanne F James; Dean Y Li; Daria A Narmoneva; Robert P Mecham; D Woodrow Benson |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-06-24 |
Journal Detail:
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Title: Circulation research Volume: 107 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2010 Aug |
Date Detail:
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Created Date: 2010-08-20 Completed Date: 2010-09-16 Revised Date: 2011-08-23 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 549-57 Citation Subset: IM |
Affiliation:
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Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. robert.hinton@cchmc.org |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Aortic Valve / abnormalities*, metabolism, pathology Disease Models, Animal* Disease Progression Elastin / deficiency*, genetics* Haploidy Heart Valve Diseases / genetics*, metabolism*, pathology Mice Mice, Inbred C57BL Mice, Mutant Strains |
| Grant Support | |
ID/Acronym/Agency:
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HD43005/HD/NICHD NIH HHS; HL69712/HL/NHLBI NIH HHS; HL74728/HL/NHLBI NIH HHS; HL85122/HL/NHLBI NIH HHS; K23 HL085122-04/HL/NHLBI NIH HHS; R01 HL077671-07/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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9007-58-3/Elastin |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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