title: Glucose lowers the threshold for human aortic vascular smooth muscle cell migration: inhibition by protein phosphatase-2A.
abstract: OBJECTIVE
  Atherosclerosis, which occurs prematurely in individuals with diabetes, incorporates vascular smooth muscle cell (VSMC) chemotaxis. Glucose, through protein kinase C-beta(II) signalling, increases chemotaxis to low concentrations of platelet-derived growth factor (PDGF)-BB. In VSMC, a biphasic response in PDGF-beta receptor (PDGF-betaR) level occurs as PDGF-BB concentrations increase. The purpose of this study was to determine whether increased concentrations of PDGF-BB and raised glucose level had a modulatory effect on the mitogen-activated protein kinase/extracellular-regulated protein kinase pathway, control of PDGF-betaR level and chemotaxis.
  
  
  METHODS
  Cultured aortic VSMC, exposed to normal glucose (NG) (5 mmol/l) or high glucose (HG) (25 mmol/l) in the presence of PDGF-BB, were assessed for migration (chemotaxis chamber) or else extracted and immunoblotted.
  
  
  RESULTS
  At concentrations of PDGF-BB <540 pmol/l, HG caused an increase in the level of PDGF-betaR in VSMC (immunoblotting) versus NG, an effect that was abrogated by inhibition of aldose reductase or protein kinase C-beta(II). At higher concentrations of PDGF-BB (>540 pmol/l) in HG, receptor level was reduced but in the presence of aldose reductase or protein kinase C-beta(II) inhibitors the receptor levels increased. It is known that phosphatases may be activated at high concentrations of growth factors. At high concentrations of PDGF-BB, the protein phosphatase (PP)2A inhibitor, endothall, caused an increase in PDGF-betaR levels and a loss of biphasicity in receptor levels in HG. At higher concentrations of PDGF-BB in HG, the chemoattractant effect of PDGF-BB was lost (chemotaxis chamber). Under these conditions inhibition of PP2A was associated with a restoration of chemotaxis to high concentrations of PDGF-BB.
  
  
  CONCLUSIONS
  The biphasic response in PDGF-betaR level and in chemotaxis to PDGF-BB in HG is due to PP2A activation.
authors.affiliation: Diabetes Research Group, Queen's University Belfast, Grosvenor Road, Belfast BT12 6BJ, UK. malcolm.campbell@qub.ac.uk
authors.forename: M
authors.initials: M
authors.lastname: Campbell
authors.forename: P
authors.initials: P
authors.lastname: Anderson
authors.forename: E R
authors.initials: ER
authors.lastname: Trimble
mesh_terms: D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D000077214:Becaplermin; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000187:drug effects*; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D000077214:Becaplermin; D020929:Mitogen-Activated Protein Kinase Kinases; D054648:Protein Phosphatase 2; D005947:Glucose