PMID- 15384957 OWN - NLM STAT- MEDLINE DCOM- 20041124 LR - 20181130 IS - 0742-3071 (Print) IS - 0742-3071 (Linking) VI - 21 IP - 10 DP - 2004 Oct TI - The effects of high glucose and atorvastatin on endothelial cell matrix production. PG - 1102-7 AB - 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. FAU - McGinn, S AU - McGinn S AD - Renal Research Group, Kolling Institute, Royal North Shore Hospital, University of Sydney, NSW, Australia. FAU - Poronnik, P AU - Poronnik P FAU - Gallery, E D M AU - Gallery ED FAU - Pollock, C A AU - Pollock CA LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Diabet Med JT - Diabetic medicine : a journal of the British Diabetic Association JID - 8500858 RN - 0 (Collagen Type IV) RN - 0 (Heptanoic Acids) RN - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors) RN - 0 (Pyrroles) RN - 0 (Tissue Inhibitor of Metalloproteinase-1) RN - 127497-59-0 (Tissue Inhibitor of Metalloproteinase-2) RN - A0JWA85V8F (Atorvastatin) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Atorvastatin MH - Blotting, Western MH - Cells, Cultured MH - Collagen Type IV/*metabolism MH - Dose-Response Relationship, Drug MH - Endothelial Cells/*metabolism MH - Extracellular Matrix/*drug effects MH - Glucose/*pharmacology MH - Heptanoic Acids/*pharmacology MH - Humans MH - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology MH - Matrix Metalloproteinase 2/metabolism MH - Pyrroles/*pharmacology MH - Tissue Inhibitor of Metalloproteinase-1/metabolism MH - Tissue Inhibitor of Metalloproteinase-2/metabolism MH - Umbilical Veins/drug effects/metabolism EDAT- 2004/09/24 05:00 MHDA- 2004/12/16 09:00 CRDT- 2004/09/24 05:00 PHST- 2004/09/24 05:00 [pubmed] PHST- 2004/12/16 09:00 [medline] PHST- 2004/09/24 05:00 [entrez] AID - DME1293 [pii] AID - 10.1111/j.1464-5491.2004.01293.x [doi] PST - ppublish SO - Diabet Med. 2004 Oct;21(10):1102-7. doi: 10.1111/j.1464-5491.2004.01293.x.