Matrix metalloproteinases-3,-7, and-12, but not-9, reduce high density lipoprotein-induced cholesterol efflux from human macrophage foam cells by truncation of the carboxyl terminus of apolipoprotein A-I - Parallel losses ofpre-beta particles and the high affinity component of efflux

Matrix metalloproteinases (MMPs) have been suggested to function in remodel ing of the arterial wall, but no information is available on their possible role in early atherogenesis, when cholesterol accumulates in the cells of the arterial intima, forming foam cells, Here, we incubated the major compo nent responsible for efflux of cholesterol from foam cells, high density li poprotein 3 (HDL3), with IMMP-1, -3, -7, -9, or -12 at 37 degrees C before adding it to cholesterol-loaded human monocyte-derived macrophages. After i ncubation with MMP-3, -7, or -12, the ability of HDL3 to induce the high af finity component of cholesterol efflux from the macrophage foam cells was s trongly reduced, whereas preincubation with MMP-1 reduced cholesterol efflu x only slightly and preincubation with MMP-9 had no effect. These different ial effects of the various MMPs were reflected in their differential abilit ies to degrade the small pre-beta migrating particles present in the HDL3 f raction. NH2-terminal sequence and mass spectrometric analyses of the apoli poprotein (apo) A-I fragments generated by MMPs revealed that those MMPs th at strongly reduced cholesterol efflux (MMPs-3, -7, and -12) cleaved the CO OH-terminal region of apoA-I and produced a major fragment of about 22 kDa, whereas MMPs-1 and -9, which had little and no effect on cholesterol efflu x, degraded apoA-I only slightly and not at all, respectively, These result s show, for the first time, that some members of the MMP family can degrade the apoA-I of HDL3, so blocking cholesterol efflux from macrophage foam ce lls. This expansion of the substrate repertoire of MMPs to include apoA sug gests that these proteinases are directly involved in the accumulation of c holesterol in atherosclerotic lesions.