Homocysteine modulates the proteolytic potential of human arterial smooth muscle cells through a reactive oxygen species dependant mechanism.
Pathological levels of homocysteine induce a dramatic degradation of arterial elastic structures. This severe metalloproteinase-dependant elastolysis affects elastic structures all over the media suggesting that smooth muscle cells (SMC) may participate to this process induced by homocysteine. Therefore, we investigated the effect of physiological (10 microM) and pathological (50, 100, and 500 microM) concentrations of homocysteine on the metalloproteinase-dependant proteolytic potential of human arterial SMC in culture. Pathological levels of homocysteine increased concomitantly the secretion of latent MMP-2 and TIMP-2 while the secretion of other elastolytic matrix metalloproteinases (MMPs) and expression of MT1-MMP were not altered. The increased secretion of latent MMP-2 induced by homocysteine was associated with an increased production of reactive oxygen species (ROS). Moreover, the increased secretion of latent MMP-2 induced by homocysteine was inhibited by antioxidant superoxide dismutase alone or in combination with catalase. These results suggest that SMC could participate, through an oxidative stress dependant secretion of elastolytic MMP-2, to the metalloproteinase-dependant degradation of arterial elastic structures induced by homocysteine.
INSERM, UMR_S 608, Université de la Méditerranée, UFR de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France.
Xue Dan
XD
Ke
Alexandrine
A
Foucault-Bertaud
Cecile
C
Genovesio
Francoise
F
Dignat-George
Edouard
E
Lamy
Philippe
P
Charpiot
D001158:Arteries / Q000166:cytology; D002478:Cells, Cultured; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D017382:Reactive Oxygen Species; D006710:Homocysteine; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2