The FASEB Journal, Vol 11, 703-711, Copyright © 1997 by The Federation of American Societies for Experimental Biology

RESEARCH COMMUNICATIONS

Homocysteine signal cascade: production of phospholipids, activation of protein kinase C, and the induction of c-fos and c-myb in smooth muscle cells

ML Dalton, PF Gadson Jr, RW Wrenn and TH Rosenquist
Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha 68195-6395, USA.

Hyperhomocysteinemia has been recognized as an independent risk factor for cerebral, coronary, and peripheral atherosclerosis. To examine the contribution of homocysteine (H[cys]) in the pathogenesis of vascular diseases, we sought to determine whether the H[cys] effect on vascular smooth muscle (VSMC) proliferation is mediated by a specific receptor/transporter or is due to an interaction with growth factors or cytokines. We show that H[cys] induced c-fos and c-myb and increased DNA synthesis 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) receptor, a glutamate-gated calcium ion channel receptor, and CGS 19755, a competitive antagonist of NMDA-type glutamate receptor. H[cys] stimulates the synthesis of mass amounts of sn-1,2 diacylglycerol, and activates protein kinase C translocation from the nucleus and cytoplasm to cell membranes. Furthermore, protein kinase C inhibitors block the growth effect mediated by H[cys]. These findings indicate that H[cys]-mediated responses are coupled to diacylglycerol- dependent protein kinase C activation. Our results suggest that homocysteine activates a receptor/transporter-like factor in neural crest derived smooth muscle.

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