Adenovirus-Mediated Overexpression of Tissue Inhibitor of Metalloproteinase-1 Reduces Atherosclerotic Lesions in Apolipoprotein E–Deficient Mice

Background —To define the role of metalloproteinases (MMPs) in the development of lipid-rich atherosclerotic lesions in relation to the balance between proteolytic and antiproteolytic activities, we investigated the impact of adenovirus-mediated elevation in the circulating levels of human tissue inhibitor of MMP (TIMP-1) in atherosclerosis-susceptible apolipoprotein E–deficient (apoE −/− ) mice. Methods and Results —Infusion of apoE −/− mice fed a lipid-rich diet with rAd.RSV.TIMP-1 (1×10 11 viral particles) resulted in high hepatic expression of TIMP-1. At 2 weeks after injection, plasma TIMP-1 levels ranged from 7 to 24 μg/mL (mean 14.8±6.8). Marked overexpression of TIMP-1 was transient, with levels of TIMP-1 decreasing to 2.5 to 8 μg/mL (mean 4.3±2.1) at 4 weeks. Plasma lipid and lipoprotein levels in mice treated with rAd.RSV.TIMP-1 were similar to those treated with rAd.RSV.βGal. However, rAd.RSV.TIMP-1–infused mice displayed a marked reduction (≈32%; P <0.05) in mean lesion area per section (512±121 μm 2 ×10 3 ; n=12 sections from 4 animals) as compared with rAd.RSV.βGal-infused mice (750±182 μm 2 ×10 3 ; n=12 sections from 4 animals). Similarly, marked reduction in macrophage deposition as well as MMP-2, MMP-3, and MMP-13 antigens was observed. Conclusions —Histological and immunohistologic analyses of atherosclerotic lesions revealed increases in collagen, elastin, and smooth muscle α-actin content in mice treated with rAd.RSV.TIMP-1. These qualitative and quantitative features were the consequence of TIMP-1 infiltration from plasma to arterial intima, as immunohistochemical analyses revealed an abundance of TIMP-1 specifically in lesions of rAd.RSV.TIMP-1–treated mice.