Elastin haploinsufficiency results in progressive aortic valve malformation and latent valve disease in a mouse model.
BACKGROUND
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.


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.
Hinton
Robert B
RB
Division of Cardiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. robert.hinton@cchmc.org
Adelman-Brown
Jennifer
J
Witt
Sandra
S
Krishnamurthy
Varun K
VK
Osinska
Hanna
H
Sakthivel
Bhuvaneswari
B
James
Jeanne F
JF
Li
Dean Y
DY
Narmoneva
Daria A
DA
Mecham
Robert P
RP
Benson
D Woodrow
DW
D000818:Animals; D001021:Aortic Valve / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004549:Elastin / Q000172:deficiency* / Q000235:genetics*; D006238:Haploidy; D006349:Heart Valve Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains
D004549:Elastin