The HMG-CoA reductase inhibitor rosuvastatin inhibits plasminogen activator inhibitor-1 expression and secretion in human adipocytes.
Human preadipocytes and adipocytes are known to produce the proatherogenic factor PAI-1 and proinflammatory cytokines, and obesity was found to be state of increased adipose production of these factors. In the present study, we investigated the effect of rosuvastatin on the regulation of PAI-1 gene expression in human adipocytes. Human preadipocytes, adipocytes in primary culture and the SGBS cell line were used as cell models. Cells were transfected using various constructs and promoter activity was measured as luciferase activity. PAI-1 expression was measured by quantitative RT-PCR and ELISA. Rosuvastatin inhibited PAI-1 mRNA expression and secretion of the protein in a concentration-dependent manner. This effect was reversed by isoprenoids. Addition of MEK-inhibitors and NFkappaB inhibitors also reduced PAI-1 expression and PAI-1 promoter luciferase activity. Further experiments revealed that rosuvastatin down-regulated the MEKK-1 mediated activation of the PAI-1 promoter. In conclusion our data suggest that rosuvastatin inhibits PAI-1 expression and release from human adipocytes via a MEKK-1-dependent but not a NFkappaB-dependent mechanism.
Laumen
Helmut
H
Else Kröner-Fresenius-Centre for Nutritional Medicine, Am Forum 5, D-85350 Freising-Weihenstephan, Technische Universität München, Germany. helmut.laumen@wzw.tum.de
Skurk
Thomas
T
Hauner
Hans
H
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology*; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D005464:Fluorobenzenes / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000502:physiology; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D009570:Nitriles / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D000068718:Rosuvastatin Calcium; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D013729:Terpenes / Q000494:pharmacology; D014162:Transfection
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007976:Leupeptins; D018942:Macrolides; D016328:NF-kappa B; D009570:Nitriles; D017395:Plasminogen Activator Inhibitor 1; D011743:Pyrimidines; D013449:Sulfonamides; D013450:Sulfones; D013729:Terpenes; C005240:monazomycin; D000068718:Rosuvastatin Calcium; D048728:MAP Kinase Kinase Kinase 1; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde