Macrophage scavenger receptors (MSR) play an important role in the pathogenesis of atherosclerosis. Therefore, modulation of MSR activity could have a beneficial effect on atherogenesis. One way to antagonize the function of a cell surface scavenger receptor is to use a soluble decoy receptor. We have constructed a soluble, chimaeric fusion protein that consists of the bovine growth hormone signal sequence and the human MSR AI extracellular domains. This secreted decoy MSR (sMSR) was cloned into an adenoviral vector and the recombinant adenoviruses were used for gene transfer experiments in vivo. We have previously shown that the secreted MSR inhibits degradation of acetylated LDL and oxidized LDL in mouse macrophages and reduces foam cell formation in vitro. We now report that in comparison to LacZ transfected control mice gene transfer with sMSR adenoviruses via tail vein injection (1 x 10(9) pfu) reduces atherosclerotic lesion area in hypercholesterolemic LDL receptor knock-out mice by 14 (P<0.05) and 19% (P=0.01), 4 and 6 weeks after the gene transfer. However, a statistically significant difference in the aortic root atherosclerosis was not detected. This is the first demonstration that the decoy sMSR can affect atherogenesis in mice after recombinant adenovirus-mediated gene transfer. Even though the achieved reduction in atherosclerosis was relatively modest the results suggest that sMSR may offer new strategies for the treatment of atherosclerosis and lipid accumulation in the vessel wall.