Faculty Collaboration Database

Elastin haploinsufficiency results in progressive aortic valve malformation and latent valve disease in a mouse model. Circ Res 2010 Aug 20;107(4):549-57

Date

06/26/2010

Pubmed ID

20576933

Pubmed Central ID

PMC2928934

DOI

10.1161/CIRCRESAHA.110.221358

Scopus ID

2-s2.0-77956226707 (requires institutional sign-in at Scopus site)   50 Citations

Abstract

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.

Author List

Hinton RB, Adelman-Brown J, Witt S, Krishnamurthy VK, Osinska H, Sakthivel B, James JF, Li DY, Narmoneva DA, Mecham RP, Benson DW

MESH terms used to index this publication - Major topics in bold

Animals
Aortic Valve
Disease Models, Animal
Disease Progression
Elastin
Haploidy
Heart Valve Diseases
Mice
Mice, Inbred C57BL
Mice, Mutant Strains