Ml. Dalton et al., HOMOCYSTEINE SIGNAL CASCADE - PRODUCTION OF PHOSPHOLIPIDS, ACTIVATIONOF PROTEIN-KINASE-C, AND THE INDUCTION OF C-FOS AND C-MYB IN SMOOTH-MUSCLE CELLS, The FASEB journal, 11(8), 1997, pp. 703-711
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.