Reduction of mouse atherosclerosis by urokinase inhibition or with a limited-spectrum matrix metalloproteinase inhibitor.
Cardiovasc Res
; 105(3): 372-82, 2015 Mar 01.
Article
en En
| MEDLINE
| ID: mdl-25616415
ABSTRACT
AIMS:
Elevated activity of urokinase plasminogen activator (uPA) and MMPs in human arteries is associated with accelerated atherosclerosis, aneurysms, and plaque rupture. We used Apoe-null mice with macrophage-specific uPA overexpression (SR-uPA mice; a well-characterized model of protease-accelerated atherosclerosis) to investigate whether systemic inhibition of proteolytic activity of uPA or a subset of MMPs can reduce protease-induced atherosclerosis and aortic dilation. METHODS ANDRESULTS:
SR-uPA mice were fed a high-fat diet for 10 weeks and treated either with an antibody inhibiting mouse uPA (mU1) or a control antibody. mU1-treated mice were also compared with PBS-treated non-uPA-overexpressing Apoe-null mice. Other SR-uPA mice were treated with one of three doses of a limited-spectrum synthetic MMP inhibitor (XL784) or vehicle. mU1 reduced aortic root intimal lesion area (20%; P = 0.05) and aortic root circumference (12%; P = 0.01). All XL784 doses reduced aortic root intimal lesion area (22-29%) and oil-red-O-positive lesion area (36-42%; P < 0.05 for all doses and both end points), with trends towards reduced aortic root circumference (6-10%). Neither mU1 nor XL784 significantly altered percent aortic surface lesion coverage. Several lines of evidence identified MMP-13 as a mediator of uPA-induced aortic MMP activity.CONCLUSIONS:
Pharmacological inhibition of either uPA or selected MMPs decreased atherosclerosis in SR-uPA mice. uPA inhibition decreased aortic dilation. Differential effects of both agents on aortic root vs. distal aortic atherosclerosis suggest prevention of atherosclerosis progression vs. initiation. Systemic inhibition of uPA or a subset of MMPs shows promise for treating atherosclerosis.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Aorta
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Enfermedades de la Aorta
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Activador de Plasminógeno de Tipo Uroquinasa
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Inhibidores de Serina Proteinasa
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Aterosclerosis
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Inhibidores de la Metaloproteinasa de la Matriz
Límite:
Animals
Idioma:
En
Revista:
Cardiovasc Res
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos