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

Weiss RM, Lund DD, Chu Y, Brooks RM, Zimmerman KA, El Accaoui R, Davis MK, Hajj GP, Zimmerman MB, Heistad DD - PLoS ONE (2013)

Bottom Line: There are no rigorously confirmed effective medical therapies for calcific aortic stenosis.Osteoprotegerin (OPG) modulates calcification in bone and blood vessels, but its effect on valve calcification and valve function is not known.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America. robert-weiss@uiowa.edu

ABSTRACT

Background: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

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Calcification in the aortic valve.Alizarin Red staining in a valve from an Older vehicle-treated mouse (A,C) demonstrates bright red staining, indicating valve calcification (arrows). Valve cusps are thickened in an Older OPG-treated mouse, but are minimally calcified (B,D). Dashed borders contain valve cusps, with care taken to exclude the aortic annulus (aa). Group data for valve calcification in Young mice (E) and Older mice (F). *p<0.05 Veh vs. OPG, N = 12.
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pone-0065201-g004: Calcification in the aortic valve.Alizarin Red staining in a valve from an Older vehicle-treated mouse (A,C) demonstrates bright red staining, indicating valve calcification (arrows). Valve cusps are thickened in an Older OPG-treated mouse, but are minimally calcified (B,D). Dashed borders contain valve cusps, with care taken to exclude the aortic annulus (aa). Group data for valve calcification in Young mice (E) and Older mice (F). *p<0.05 Veh vs. OPG, N = 12.

Mentions: OPG attenuated calcification of valve tissue in Young mice and in Older mice by about 70% (Figure 4). OPG also attenuated accumulation of the bone matrix-specific protein, osteocalcin, in the aortic valve of Older mice by about 80% (Figure 5).


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

Weiss RM, Lund DD, Chu Y, Brooks RM, Zimmerman KA, El Accaoui R, Davis MK, Hajj GP, Zimmerman MB, Heistad DD - PLoS ONE (2013)

Calcification in the aortic valve.Alizarin Red staining in a valve from an Older vehicle-treated mouse (A,C) demonstrates bright red staining, indicating valve calcification (arrows). Valve cusps are thickened in an Older OPG-treated mouse, but are minimally calcified (B,D). Dashed borders contain valve cusps, with care taken to exclude the aortic annulus (aa). Group data for valve calcification in Young mice (E) and Older mice (F). *p<0.05 Veh vs. OPG, N = 12.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675204&req=5

pone-0065201-g004: Calcification in the aortic valve.Alizarin Red staining in a valve from an Older vehicle-treated mouse (A,C) demonstrates bright red staining, indicating valve calcification (arrows). Valve cusps are thickened in an Older OPG-treated mouse, but are minimally calcified (B,D). Dashed borders contain valve cusps, with care taken to exclude the aortic annulus (aa). Group data for valve calcification in Young mice (E) and Older mice (F). *p<0.05 Veh vs. OPG, N = 12.
Mentions: OPG attenuated calcification of valve tissue in Young mice and in Older mice by about 70% (Figure 4). OPG also attenuated accumulation of the bone matrix-specific protein, osteocalcin, in the aortic valve of Older mice by about 80% (Figure 5).

Bottom Line: There are no rigorously confirmed effective medical therapies for calcific aortic stenosis.Osteoprotegerin (OPG) modulates calcification in bone and blood vessels, but its effect on valve calcification and valve function is not known.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Cardiovascular Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America. robert-weiss@uiowa.edu

ABSTRACT

Background: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus