Cerivastatin, a HMG-CoA reductase inhibitor, reduces plasminogen activator inhibitor-1 (PAI-1) expression in endothelial cells by down-regulation of cellular signaling and the inhibition of PAI-1 promoter activity.
Statins, which competitively inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity and reduce mevalonate synthesis, are believed to exert a plethora of pleiotropic effects. In this report, molecular mechanisms of the inhibitory effect on plasminogen activator inhibitor type 1 (PAI-1) expression produced by cerivastatin (CRV), the most active compound in this class, were studied using monocultures of human endothelial cell line (EA.hy 926). CRV similar to another statin, lovastatin (LOV), significantly inhibited PAI-1 expression and its release from endothelial cells, nonstimulated and stimulated with TNF-alpha. The inhibitory effect of CRV could be detected at the level of PAI-1 promoter in EA.hy 926 cells transfected with plasmid p800 LUC containing PAI-1 promoter fragment (+71 to -800), as well as at the level of PAI-1 mRNA. The PAI-1 promoter activity was markedly suppressed in the nonstimulated cells and almost completely inhibited in TNF-alpha-stimulated cells. In addition, CRV at low doses (IC(50) of 4 - 6 microM) significantly inhibited mitogen-activated protein kinases (MAPKs) phosphorylation. The majority of inhibitory effects occurred at significantly lower concentrations for CRV compared to LOV. The mechanism by which CRV inhibits PAI-1 expression appears to be directly associated with geranylgeranylation of some cell proteins, since the inhibitory effect on PAI-1 expression can be reversed by geranylgeranyl-pyrophosphate but not by farnesyl-pyrophosphate.
Swiatkowska
Maria
M
Department of Molecular and Medical Biophysics, Medical University of Lodz, Poland.
Pawlowska
Zofia
Z
Szemraj
Janusz
J
Drzewoski
Józef
J
Watala
Cezary
C
Cierniewski
Czeslaw S
CS
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008148:Lovastatin / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D012717:Sesquiterpenes; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D011106:Polyisoprenyl Phosphates; D011725:Pyridines; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; C004808:farnesyl pyrophosphate; D008148:Lovastatin; C086276:cerivastatin; D020928:Mitogen-Activated Protein Kinases; C002963:geranylgeranyl pyrophosphate