title: The effects of high glucose and atorvastatin on endothelial cell matrix production.
abstract: BACKGROUND
  Statins are known to enhance atherosclerotic plaque stability through influences on extracellular matrix homeostasis. Net matrix production reflects the relative balance of matrix production and degradation through enzymes such as matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitor of MMP (TIMPs). The effects of statins on endothelial cell production of these parameters following co-exposure with a proatherogenic stimulus such as high glucose are not known.
  
  
  METHODS
  Human endothelial cells were exposed for 72 h to 5 mm (control) or 25 mm (high) glucose +/- atorvastatin (1 micromol/l). Extracellular matrix homeostasis was assessed by measuring matrix metalloproteinase (MMP)-2 secretion, tissue inhibitor of MMP (TIMP)-1 and -2 secretion and net collagen IV production. Results were expressed as percentage +/- SEM of control values.
  
  
  RESULTS
  Exposure to high glucose increased cellular collagen IV expression to 190.1 +/- 11.7% (P < 0.0001) of control levels. No change in MMP-2 secretion (111.6 +/- 5.2%; P > 0.05) was observed but both TIMP-1 and TIMP-2 expression were increased to 136.3 +/- 6.4% and 144.0 +/- 27.5%, respectively (both P < 0.05). The presence of atorvastatin in high glucose conditions reduced collagen IV expression to 136.1 +/- 20.6%. This was paralleled by increased secretion of MMP-2 to 145.8 +/- 7.8% (P < 0.01), increased TIMP-2 expression to 208.0 +/- 21.3% (P < 0.005 compared with high glucose) but no change in TIMP-1 expression (155.1 +/- 14.6%) compared with high glucose alone. The presence of atorvastatin in control conditions did not affect levels of collagen IV expression (114.5 +/- 13.2%).
  
  
  CONCLUSIONS
  Endothelial cell exposure to high glucose was associated with a MMP/TIMP profile that increased extracellular matrix production which was attenuated by concurrent exposure to atorvastatin. Consequently, a mechanism by which the atherosclerotic plaque regression that is observed in patients taking these drugs has been demonstrated.
authors.affiliation: Renal Research Group, Kolling Institute, Royal North Shore Hospital, University of Sydney, NSW, Australia.
authors.forename: S
authors.initials: S
authors.lastname: McGinn
authors.forename: P
authors.initials: P
authors.lastname: Poronnik
authors.forename: E D M
authors.initials: ED
authors.lastname: Gallery
authors.forename: C A
authors.initials: CA
authors.lastname: Pollock
mesh_terms: D000069059:Atorvastatin; D015153:Blotting, Western; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism*; D005109:Extracellular Matrix / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism
chemical_list: D024141:Collagen Type IV; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D000069059:Atorvastatin; D020778:Matrix Metalloproteinase 2; D005947:Glucose