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 developme nt 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 inh ibitor of MMP (TIMP-1) in atherosclerosis-susceptible apolipoprotein E-defi cient (apoE(-/-)) mice. Methods and Results-Infusion of apoE(-/-) mice fed a lipid-rich diet with r Ad.RSV.TIMP-1 (1X10(11) viral particles) resulted in high hepatic expressio n of TIMP-1. At 2 weeks after injection, plasma TIMP-1 levels ranged from 7 to 24 mu g/mL (mean 14.8+/-6.8), Marked overexpression of TIMP-1 was trans ient, with levels of TIMP-1 decreasing to 2.5 to 8 mu g/mL (mean 4.3+/-2.1) at 4 weeks. Plasma lipid and lipoprotein levels in mice treated with rAd.R SV.TIMP-1 were similar to those treated with rAd.RSV.beta Gal. However, rAd .RSV.TIMP-1-infused mice displayed a marked reduction (approximate to 32%; P<0.05) in mean lesion area per section (512+/-121 mu m(2)X10(3); n=12 sect ions from 4 animals) as compared with rAd.RSV.beta Gal-infused mice (750+/- 182 mu m(2)x10(3); n=12 sect:ions from 4 animals). Similarly, marked reduct ion in macrophage deposition as well as MMP-2, MMP-3, and MMP-13 antigens w as observed. Conclusions-Histological and immunohistologic analyses of atherosclerotic l esions revealed increases in collagen, elastin, and smooth muscle alpha-act in content in mice treated with rAd.RSV.TIMP-1. These qualitative and quant itative 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-l-treated mice.