ERK2 ACTIVATION BY HOMOCYSTEINE IN VASCULAR SMOOTH-MUSCLE CELLS

Homocysteine at abnormally high levels is an independent risk factor f or atherosclerosis and may be a key factor in atherogenesis. Since hom ocysteine (Hcys) has been shown to promote cell proliferation and indu ction of the gene transcription factor c-fos in vascular smooth muscle cells (VSMCs), effects which can be mediated by MAP kinase, we hypoth esized that homocysteine activates a MAP kinase-dependent signal trans duction pathway. In this study, we find that homocysteine transiently activates MAP kinase (ERK2 isoform) in cultured VSMCs from chick embry os. Homocysteine activation of ERK2 is dose-dependent with an EC50 of approximately 500 nM and blocked by the MAP/Erk kinase (MEK) inhibitor PD98059. VSMC embryonic lineage is another determinant of homocystein e sensitivity. These findings demonstrate that homocysteine activates the MAP kinase signal transduction pathway and thus support the hypoth esis that homocysteine may promote atherosclerosis by stimulation of g rowth promoting signal transduction pathways. (C) 1998 Academic Press.