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Osteoprotegerin inhibits aortic valve calcification and preserves valve function in hypercholesterolemic mice
Journal article   Open access   Peer reviewed

Osteoprotegerin inhibits aortic valve calcification and preserves valve function in hypercholesterolemic mice

Robert M Weiss, Donald D Lund, Yi Chu, Robert M Brooks, Kathy A Zimmerman, Ramzi El Accaoui, Melissa K Davis, Georges P Hajj, M Bridget Zimmerman and Donald D Heistad
PloS one, Vol.8(6), pp.e65201-e65201
2013
DOI: 10.1371/journal.pone.0065201
PMCID: PMC3675204
PMID: 23762316
url
https://doi.org/10.1371/journal.pone.0065201View
Published (Version of record) Open Access

Abstract

There are no rigorously confirmed effective medical therapies for calcific aortic stenosis. Hypercholesterolemic Ldlr (-/-) Apob (100/100) mice develop calcific aortic stenosis and valvular cardiomyopathy in old age. Osteoprotegerin (OPG) modulates calcification in bone and blood vessels, but its effect on valve calcification and valve function is not known. To determine the impact of pharmacologic treatment with OPG upon aortic valve calcification and valve function in aortic stenosis-prone hypercholesterolemic Ldlr (-/-) Apob (100/100) mice. Young Ldlr (-/-) Apob (100/100) mice (age 2 months) were fed a Western diet and received exogenous OPG or vehicle (N = 12 each) 3 times per week, until age 8 months. After echocardiographic evaluation of valve function, the aortic valve was evaluated histologically. Older Ldlr (-/-) Apob (100/100) mice were fed a Western diet beginning at age 2 months. OPG or vehicle (N = 12 each) was administered from 6 to 12 months of age, followed by echocardiographic evaluation of valve function, followed by histologic evaluation. In Young Ldlr (-/-) Apob (100/100) mice, OPG significantly attenuated osteogenic transformation in the aortic valve, but did not affect lipid accumulation. In Older Ldlr (-/-) Apob (100/100) mice, OPG attenuated accumulation of the osteoblast-specific matrix protein osteocalcin by ∼80%, and attenuated aortic valve calcification by ∼ 70%. OPG also attenuated impairment of aortic valve function. OPG attenuates pro-calcific processes in the aortic valve, and protects against impairment of aortic valve function in hypercholesterolemic aortic stenosis-prone Ldlr (-/-) Apob (100/100) mice.
 Hypercholesterolemia - diagnostic imaging Aortic Valve Stenosis - drug therapy Age Factors Aortic Valve - drug effects Calcinosis - diagnostic imaging Male Hypercholesterolemia - drug therapy Aortic Valve - pathology Aortic Valve Stenosis - diagnostic imaging Hypercholesterolemia - pathology Receptors, LDL - deficiency Ultrasonography Female Calcinosis - metabolism Disease Models, Animal Receptors, LDL - genetics Calcinosis - drug therapy Aortic Valve - diagnostic imaging Osteogenesis - drug effects Osteoprotegerin - pharmacology Mice, Transgenic Apolipoprotein B-100 - genetics Aortic Valve - metabolism Injections Animals Aortic Valve Stenosis - pathology Aortic Valve Stenosis - metabolism Mice Calcinosis - pathology Hypercholesterolemia - metabolism

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