ERK2 activation by homocysteine in vascular smooth muscle cells.
Homocysteine at abnormally high levels is an independent risk factor for atherosclerosis and may be a key factor in atherogenesis. Since homocysteine (Hcys) has been shown to promote cell proliferation and induction of the gene transcription factor c-fos in vascular smooth muscle cells (VSMCs), effects which can be mediated by MAP kinase, we hypothesized that homocysteine activates a MAP kinase-dependent signal transduction pathway. In this study, we find that homocysteine transiently activates MAP kinase (ERK2 isoform) in cultured VSMCs from chick embryos. 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 homocysteine sensitivity. These findings demonstrate that homocysteine activates the MAP kinase signal transduction pathway and thus support the hypothesis that homocysteine may promote atherosclerosis by stimulation of growth promoting signal transduction pathways.
Brown
J C
JC
Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska, 68198-6260, USA.
Rosenquist
T H
TH
Monaghan
D T
DT
D000005:Abdomen / Q000098:blood supply; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002478:Cells, Cultured; D002642:Chick Embryo; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005419:Flavonoids; D006710:Homocysteine / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D013909:Thorax / Q000098:blood supply
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005419:Flavonoids; D016194:Receptors, N-Methyl-D-Aspartate; D006710:Homocysteine; D016291:Dizocilpine Maleate; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one