Differential effects of gemfibrozil on migration, proliferation and proteoglycan production in human vascular smooth muscle cells.
The aim of this study was to determine, if gemfibrozil has anti-atherogenic actions on human vascular smooth muscle cells (SMCs) and whether these actions are affected by high glucose concentrations, which mimic the hyperglycemia of diabetes. Proliferation of SMCs treated with gemfibrozil was estimated by cell counting (Coulter Counter) and [3H]thymidine incorporation, migration in a scrape-wound assay, proteoglycan (PG) biosynthesis and glycosaminoglycan (GAG) synthesis on xyloside by [35S]sulfate labeling and sizing by sodium dodecyl sulphide-polyacrylamide gel electrophoresis (SDS-PAGE). Gemfibrozil (100 micromol/l) did not affect migration in low or high glucose media. Gemfibrozil caused concentration-dependent inhibition of proliferation in low glucose media (24% inhibition at 100 micromol/l, P<0.01) and inhibited the re-initiation of DNA synthesis by 33.3% (100 micromol/l, P<0.05) in low glucose and 31.4% (100 micromol/l, P<0.001) in high glucose conditions. In low and high glucose media, gemfibrozil (100 micromol/l) reduced total PG production in the presence of TGF-beta 1, which was associated with a decrease in the apparent size of PGs. Gemfibrozil and another PPAR-alpha ligand, WY-14643, significantly inhibited basal and TGF-beta1 stimulated GAG synthesis. We conclude that some SMCs properties associated with atherogenesis are favorably affected by gemfibrozil. Hence, direct vascular actions of gemfibrozil observed in this study may contribute to the reduction in cardiovascular disease observed in clinical studies with gemfibrozil.
Nigro
Julie
J
Cell Biology of Diabetes Laboratory, Baker Medical Research Institute, St. Kilda Road Central, PO Box 6492, Melbourne, Vic. 8008, Australia.
Dilley
Rodney J
RJ
Little
Peter J
PJ
D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D015248:Gemfibrozil / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000096:biosynthesis; D006027:Glycosides / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D011509:Proteoglycans / Q000096:biosynthesis* / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000494:pharmacology; D016896:Treatment Outcome
D006025:Glycosaminoglycans; D006027:Glycosides; D000960:Hypolipidemic Agents; D011509:Proteoglycans; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C010807:xylosides; C006253:pirinixic acid; D004247:DNA; D005947:Glucose; D015248:Gemfibrozil