title: Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine.
abstract: Although hyperhomocysteinemia has been recognized recently as a prevalent risk factor for myocardial infarction and stroke, the mechanisms by which it accelerates arteriosclerosis have not been elucidated, mostly because the biological effects of homocysteine can only be demonstrated at very high concentrations and can be mimicked by cysteine, which indicates a lack of specificity. We found that 10-50 microM of homocysteine (a range that overlaps levels observed clinically) but not cysteine inhibited DNA synthesis in vascular endothelial cells (VEC) and arrested their growth at the G1 phase of the cell cycle. Homocysteine in this same range had no effect on the growth of vascular smooth muscle cells (VSMC) or fibroblasts. Homocysteine decreased carboxyl methylation of p21(ras) (a G1 regulator whose activity is regulated by prenylation and methylation in addition to GTP-GDP exchange) by 50% in VEC but not VSMC, a difference that may be explained by the ability of homocysteine to dramatically increase levels of S-adenosylhomocysteine, a potent inhibitor of methyltransferase, in VEC but not VSMC. Moreover, homocysteine-induced hypomethylation in VEC was associated with a 66% reduction in membrane-associated p21(ras) and a 67% reduction in extracellular signal-regulated kinase 1/2, which is a member of the mitogen-activated protein (MAP) kinase family. Because the MAP kinases have been implicated in cell growth, the p21(ras)-MAP kinase pathway may represent one of the mechanisms that mediates homocysteine's effect on VEC growth. VEC damage is a hallmark of arteriosclerosis. Homocysteine-induced inhibition of VEC growth may play an important role in this disease process.
authors.affiliation: Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Yoshizumi
authors.forename: K
authors.initials: K
authors.lastname: Lai
authors.forename: J C
authors.initials: JC
authors.lastname: Tsai
authors.forename: M A
authors.initials: MA
authors.lastname: Perrella
authors.forename: E
authors.initials: E
authors.lastname: Haber
authors.forename: M E
authors.initials: ME
authors.lastname: Lee
mesh_terms: D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003545:Cysteine / Q000494:pharmacology*; D004247:DNA / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D005434:Flow Cytometry; D016193:G1 Phase; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008745:Methylation; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D013997:Time Factors; D014471:Umbilical Veins
chemical_list: D006710:Homocysteine; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D004247:DNA; D012435:S-Adenosylhomocysteine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D003545:Cysteine