HOMOCYSTEINE SIGNAL CASCADE - PRODUCTION OF PHOSPHOLIPIDS, ACTIVATIONOF PROTEIN-KINASE-C, AND THE INDUCTION OF C-FOS AND C-MYB IN SMOOTH-MUSCLE CELLS

Hyperhomocysteinemia has been recognized as an independent risk factor far cerebral, coronary, and peripheral atherosclerosis, To examine th e contribution of homocysteine (H[cys]) in the pathogenesis of vascula r diseases, we sought to determine whether the H[cys] effect on vascul ar smooth muscle (VSMC) proliferation is mediated by a specific recept or/transporter or is due to an interaction with growth factors or cyto kines. We show that H[cys] induced c-fos and c-myb and increased DNA s ynthesis and cell proliferation 12-fold in neural crest-derived VSMC ( N-VSMC). The H[cys] effect on N-VSMC proliferation is inhibited by Mk- 801, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) re ceptor, a glutamate-gated calcium ion channel receptor, and CGS 19755, a competitive antagonist of NMDA-type glutamate receptor. H[cys] stim ulates the synthesis of mass amounts of sn-1,2 diacylglycerol, and act ivates protein kinase C translocation from the nucleus and cytoplasm t o cell membranes. Furthermore, protein kinase C inhibitors block the g rowth effect mediated by H[cys]. These findings indicate that H[cys]-m ediated responses are coupled to diacylglycerol-dependent protein kina se C; activation. Our results suggest that homocysteine activates a re ceptor/transporter-like factor in neural crest derived smooth muscle.