title: Homocysteine promotes p38-dependent chemotaxis in bovine aortic smooth muscle cells.
abstract: OBJECTIVE
  Increased levels of homocysteine in the blood are a risk factor for atherosclerosis. The purpose of this study was to examine the effects of homocysteine on smooth muscle cell (SMC) migration and to determine whether p38 was involved in this process.
  
  
  METHODS
  The effect of 0.5 to 2.0 mmol/L d , l -homocysteine as a chemoattractant for SMCs was assayed with a modified Boyden chamber. To determine the functional role of p38 in SMC chemotaxis induced by d , l -homocysteine, we treated SMCs with a p38 inhibitor, SB203580, before the assay.
  
  
  RESULTS
  The number of migrated cells was increased 7.0 +/- 1.2-fold (n = 15; P < .001) by 2.0 mmol/L d , l -homocysteine. SB203580 partially prevented the migration of SMCs toward homocysteine. Preconditioning SMCs with 2.0 mmol/L d , l -homocysteine significantly enhanced chemotaxis toward 10% fetal bovine serum compared with nonconditioned control SMCs (28.9 +/- 3.3-fold vs 15.6 +/- 2.8-fold; P < .05). There was a fourfold p38 activation after exposure of SMCs to 2.0 mmol/L d , l -homocysteine by immunoblot.
  
  
  CONCLUSIONS
  These results suggest that homocysteine not only is a chemoattractant for SMC but can also enhance SMC chemotactic potential. The mechanism of these effects may involve p38 activation.
  
  
  CONCLUSIONS
  This study demonstrates that homocysteine can promote chemotaxis of SMCs through a p38-dependent pathway. To our knowledge, this is the first report that homocysteine may influence SMC chemotaxis. It may be an important mechanism for homocysteine-induced atherogenesis, because the migration of SMCs from the media is believed to play a critical role in progressive intimal thickening. Although homocysteine promotes atherogenesis and thrombosis by a variety of mechanisms, the effects of homocysteine on SMC proliferation and migration might be critical elements that may have potential therapeutic implications, because selective blockade of the p38 pathway is feasible.
authors.affiliation: Department of Surgery, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Akasaka
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Akasaka
authors.forename: Gabriel
authors.initials: G
authors.lastname: Di Luozzo
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Sasajima
authors.forename: Bauer E
authors.initials: BE
authors.lastname: Sumpio
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002417:Cattle; D002633:Chemotaxis / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006710:Homocysteine / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D006710:Homocysteine; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580