Regulation of MMP-1 expression in vascular endothelial cells by insulin sensitizing thiazolidinediones.
Matrix metalloproteinases (MMPs) have been implicated in the disruption of atherosclerotic plaques that leads to acute coronary events. The present study investigates the effect of thiazolidinediones (TZDs), new antidiabetic drugs, on MMP-1 expression by human vascular endothelial cells. Results show that troglitazone, but not pioglitazone and rosiglitazone, stimulated MMP-1 secretion and mRNA expression in both human umbilical vein and aortic endothelial cells, but had no effect on TIMP-1 and TIMP-2 secretion. Interestingly, troglitazone at high concentrations (> or = 30 micromol/l) inhibited MMP-1 protein synthesis despite a marked stimulation on MMP-1 mRNA. Further studies revealed that troglitazone at higher concentrations inhibits de novo protein synthesis as determined by 35S-methionine/cysteine incorporation, suggesting that the inhibition of MMP-1 synthesis by troglitazone is due to the suppression of total protein synthesis. Finally, our studies showed that high concentrations of troglitazone inhibited the translation initiation factor 4E (eIF4E), but not eIF4G. In summary, the present study demonstrates that insulin sensitizers have different effects on MMP-1 expression, and troglitazone stimulates MMP-1 mRNA expression and protein synthesis at the pharmacological concentrations, but inhibits MMP-1 synthesis at higher doses. This study also suggests that supra-pharmacological concentrations of troglitazone that could be attained in body tissues may inhibit protein synthesis and cause cytotoxicity.
Game
Bryan A
BA
Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Ralph H. Johnson Veterans Affairs Medical Center, 114 Doughty St., Charleston, SC 29403, USA.
Xu
Minfu
M
Lopes-Virella
Maria F
MF
Huang
Yan
Y
D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D003545:Cysteine / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology*; D004797:Enzyme-Linked Immunosorbent Assay; D039642:Eukaryotic Initiation Factors / Q000037:antagonists & inhibitors; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D015151:Immunoblotting; D020781:Matrix Metalloproteinase 1 / Q000032:analysis / Q000096:biosynthesis / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D008715:Methionine / Q000378:metabolism; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000032:analysis; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone; D014471:Umbilical Veins / Q000166:cytology
D002839:Chromans; D039642:Eukaryotic Initiation Factors; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D008715:Methionine; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1; D000077288:Troglitazone; D003545:Cysteine; D000077205:Pioglitazone