Whether fatty streaks are directly followed by fibrous plaque formation in atherosclerosis remains controversial. Disruption of the basement membrane and elastic layers is thought to be essential for this process. Matrix metalloproteinase 12 (MMP-12) can degrade a broad spectrum of substrates, but the role of MMP-12 in the early stage of atherosclerosis is unclear. To investigate MMP-12 function in the initiation and progression of atherosclerosis, we investigated macrophage migration and elastolysis in relation to fatty streaks in human MMP-12 transgenic (hMMP-12 Tg) rabbits. Fatty streaks in hMMP-12 Tg rabbits fed a 1% cholesterol diet for 6 weeks (cholesterol-induced model of atherosclerosis) were more pronounced and were associated with more significant degradation of the internal elastic layer compared with wild-type (WT) animals. Numbers of infiltrating macrophages and smooth muscle cells in the lesions were increased in hMMP-12 Tg compared with WT animals. In both cuff- and ligation-induced models of atherosclerosis, smooth muscle cell-predominant atherosclerotic lesions were elevated with significant elastolysis of the internal elastic lamina in Tg compared with WT animals; "microelastolytic sites" were recognized before formation of the neointima in the cuff model only. These results indicate that MMP-12 may be critical to the initiation and progression of atherosclerosis via degradation of the elastic layers and/or basement membrane. Therefore, a specific MMP-12 inhibitor might prove useful for the treatment of progressive atherosclerosis.