Homocysteine signal cascade: production of phospholipids, activation of 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 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.
Dalton
M L
ML
Department of Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha 68195-6395, USA.
Gadson
P F
PF
Wrenn
R W
RW
Rosenquist
T H
TH
D001012:Aorta, Abdominal / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D001013:Aorta, Thoracic / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000209:etiology / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000096:biosynthesis; D004075:Diglycerides / Q000096:biosynthesis*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D016762:Genes, fos / Q000187:drug effects / Q000235:genetics*; D018698:Glutamic Acid / Q000494:pharmacology; D006710:Homocysteine / Q000031:analogs & derivatives / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D015151:Immunoblotting; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D016202:N-Methylaspartate / Q000494:pharmacology; D009857:Oncogenes / Q000187:drug effects / Q000235:genetics*; D010875:Pipecolic Acids / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D011493:Protein Kinase C / Q000378:metabolism*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
C011439:1,2-diacylglycerol; D004075:Diglycerides; D018691:Excitatory Amino Acid Antagonists; D010875:Pipecolic Acids; D016194:Receptors, N-Methyl-D-Aspartate; D006710:Homocysteine; C007956:homocysteic acid; D018698:Glutamic Acid; C053672:selfotel; D012313:RNA; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D004247:DNA; D011493:Protein Kinase C