Meprin is a member of the astacin family of zinc metalloendopeptidases. It is widely distributed in the body, and hydrolyzes and inactivates several endogenous vasoactive peptides, some of which could alter various functions of cells in the arterial wall. We assessed the influence of chronic meprin inhibition by daily administration of actinonin (5mg/kg body weight per day; i.p.) on the development of atherosclerotic changes in ApoE(-/-) mice. Mice were fed a high-fat (21% fat), cholesterol-rich (1% cholesterol) Western-type diet for 16 weeks starting at 10 weeks of age. At 20 weeks of age, randomly selected ApoE(-/-) mice were treated with Western-type diet chow pellets supplemented with commercially available actinonin (meprin-I group) for 6 weeks; the diet of control ApoE(-/-) mice was supplemented with saline (placebo group). There was no difference in body weight, hemodynamic data and serum lipids between the two groups at the end of the dietary period. Meprin-I treatment was found to elevate levels of natriuretic peptides (NPs) in plasma and the vascular wall by radioimmunoassay. Meprin-I treatment also decreased plaque volume and suppressed lipid deposition in carotid arteries. Meprin-I treatment reduced production of reactive oxygen species (ROS) and apoptosis (which are associated with atherosclerosis) in the vascular wall. In in vitro experiments, meprin-I treatment increased NP function on cell apoptosis, proliferation, and intracellular ROS generation in the THP-1 cell line and primary vascular smooth muscle cells (VSMC). These results suggest that the meprin inhibitor actinonin may have a protective role in atherosclerosis, and that meprin inhibition may be therapeutically useful in atherosclerosis prevention. Suppression of degradation in the arteries of endogenously released NPs (particularly atrial natriuretic peptide and brain natriuretic peptide), or other kinins known to have anti-atherosclerotic actions, may at least partially contribute to the inhibitory effects of meprin-I on atherosclerotic changes.