Abstract 5489: Treatment of ApoE-Deficient Mice with Statin Inhibits the Oxidative Stress-Dependent Lysosomal Protease Cathepsin Activation System: Implication for Plaque Stability
Lysosomal protease cathepsin (Cat) overexpressed in atherosclerotic lesions has a strong proteolytic activity. Given that reactive oxygen species (ROS) are also implicated in protease activation in atherogenesis, we examined a possible role of the ROS-induced cathepsin activation system in neointima formation and atherosclerotic plaque in stability. Murine vascular injury-induced neointima formation was examined by use of a carotid artery ligation model, which demonstrated that cathepsin K deficiency impaired neointima formation and that cystatin C deficiency enhanced it (9-week-old males; n = 18 for each group, P<0.01). To examine statin-mediated pleiotropic actions on neointima formation and plaque stability, a mouse plaque disruption model (a combination of ligation and cuff placement treatment) was applied to apoE-deficient mice (9-week-old males). The apoE-deficient mice (n = 24–30 for each group) maintained on a normal diet were treated with (1) vehicle (0.5% carboxymethyl cellulose), pitavastatin (1 mg/kg/d), pitavastatin (10 mg/kg/d) for 10 days (before and after cuff treatment; all given by oral gavage every day). Pitavastatin suppressed not only macrophage infiltration but also levels of NADPH oxidase component mRNAs (p22phox and gp91 phox) and O2-production in the atherosclerotic lesions. Moreover, pitavastatin increased the collagen fraction and reduced media elastic lamina fragmentation concomitant with decreases in the levels of cathepsin K mRNA and protein. Among these beneficial effects, high doses of pitavastatin further reduced intraplaque hemorrhage. The pitavastatin-mediated vascular-protective effects were mimicked by cathepsin K deficiency in apoE-deficient mice. Pitavastatin lowered the serum levels of cathepsin K but not plasma lipid profile. Pitavastatin inhibited H2O2-induced Cat K expression and activity in cultured smooth muscle cells and macrophages. Cathepsin K deficiency suppressed vascular injury-induced neointima formation. The data suggested that short-term administration of statin attenuates neointima formation and atherosclerotic plaque stability at least in part by inhibiting the oxidative stress-dependent Cat activation system.