Abstract 138: Treatment of Atherosclerosis by Systemic Protease Inhibition
Background Elevated activity of urokinase plasminogen activator (uPA) and matrix metalloproteases (MMPs) in human arteries is associated with accelerated atherosclerosis (athero), aneurysms, and plaque rupture. Apoe-null mice with macrophage-targeted uPA overexpression (SR-uPA mice) have elevated vascular uPA and MMP activity, accelerated athero, dilated aortic roots, and increased histologic features of plaque rupture. SR-uPA mice are therefore a useful experimental setting for beginning to investigate whether inhibition of uPA or MMPs can prevent athero progression, aortic dilation, and plaque rupture.
Hypothesis Treatment with a murine monoclonal antibody inhibiting mouse uPA (mU1), or a limited-spectrum synthetic MMP inhibitor (XL784) will reduce athero in SR-uPA mice.
Methods SR-uPA mice were fed a high-fat diet for 10 wk beginning at 5 - 6 wk of age. Fat-fed mice were injected with mU1 or control antibody twice per wk (for 10 wk), or were given either XL784 (125, 250, or 500 mg/kg) or vehicle by daily oral gavage. Mice were then anesthetized, formalin-perfused, and athero was measured in isolated aortic roots and pinned aortas. Groups were compared by t-test and ANOVA.
Results None of the treatments altered peripheral blood monocyte counts or plasma cholesterol. mU1 reduced aortic root intimal lesion area by 20% (P < 0.05) and aortic root circumference by 12% (P = 0.01). All 3 doses of XL784 significantly decreased oil-red O-positive lesion area (36 - 42%; P < 0.05 for all). All XL784 doses also reduced aortic root intimal lesion area (22 - 29%; P < 0.05 for low dose only). The highest XL784 dose also reduced total macrophage-positive lesion area (33%; P < 0.05). All XL784 doses yielded trends towards decreased aortic root circumference (5 - 10%). Neither mU1 nor XL784 significantly altered percent aortic surface lesion coverage.
Conclusions In SR-uPA mice, pharmacologic inhibition of either uPA or selected MMPs significantly decreased aortic root athero and limited aortic dilation. Differential effects of both agents on aortic root versus surface athero suggest prevention of athero progression rather than initiation. These approaches to protease inhibition show promise for preventing the progression and complications of established athero.
- © 2013 by American Heart Association, Inc.