Influence of homocysteine on matrix metalloproteinase-2: Activation and activity

Increased levels of the physiological amino acid homocysteine (Hcy) are con sidered a risk factor for vascular disease. Hyperhomocysteinemia causes an intense remodelling of the extracellular matrix in arterial walls, particul arly an elastolysis involving metalloproteinases. We investigated the activ ation of the latent elastolytic metalloproteinase proMMP-2 (72 kDa) by Hcy. Hcy was proved to exert a dual effect, activating proMMP-2 at low molar ra tio (MR 10:1) and inhibiting active MMP2 at high molar ratio (MR > 1000:1). Methionine and the disulphide homocystine did not activate nor inhibit MMP -2, showing that the activation as well as the inhibition requires the thio l group to be free. The activation of proMMP-2 by Hcy is in accordance with the "cysteine-switch" mechanism, but occurs without further autoproteolysi s of the enzyme molecule. In contrast with Hcy, the other physiological thi ol compounds cysteine and reduced glutathione did not activate proMMP-2. Th ese results suggest that the direct activation of proMMP2 by Hcy could be o ne of the mechanisms involved in the extracellular matrix deterioration in hyperhomocysteinemia-associated arteriosclerosis. (C) 1999 Academic Press.