EXPRESSION AND LOCALIZATION OF MATRIX METALLOPROTEINASE-12 IN THE AORTA OF CHOLESTEROL-FED RABBITS - RELATIONSHIP TO LESION DEVELOPMENT

Degradation of extracellular matrix (ECM) proteins in the aorta is a c ritical step for the development of atherosclerosis. Expression of mat rix metalloproteinase (MMP)-12 (macrophage elastase), an elastin-degra ding proteinase in the MMP family, was investigated in the thoracic ao rta of rabbits fed a 1% cholesterol-containing diet for 16 weeks. In t he atherosclerotic lesions, MMP-12 was produced abundantly at both the mRNA and protein levels, whereas no expression was observed in the no rmal rabbit aortas. The principal source of MMP-12 was macrophage foam cells (MFCs) that had infiltrated the atherosclerotic intima; this wa s demonstrated in both in vitro culture studies of MFCs purified from atherosclerotic lesions and immunohistochemical studies of aortic lesi ons. Additional biochemical studies using recombinant rabbit MMP-12 re vealed that MMP-12 digested elastin, type IV collagen, and fibronectin and also activated MMP-2 and MMP-3. Expression of MMP-12 by human mac rophage cell lines was increased by stimulation with acetylated low-de nsity lipoprotein, implying augmentation of MMP-12 production during f oam cell formation. Increased expression of MMP-12 in atherosclerotic lesions, concomitant with foam cell generation, which triggers the acc eleration of ECM breakdown, is likely to be a critical step in the ini tiation and progression of the atherosclerotic cascade.