Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Zirlik, A; Ernst, S; Leugers, A; Willecke, F; Sobel, BE; Bode, C; Nordt, TK.
Inhibition by fibrates of plasminogen activator inhibitor type-1 expression in human adipocytes and preadipocytes.
THROMB HAEMOSTASIS. 2009; 101(6): 1060-1069.
Doi: 10.1160/TH08-03-0164
Web of Science
PubMed
FullText
FullText_MUG
- Führende Autor*innen der Med Uni Graz
- Zirlik Andreas
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- Abstract:
- Plasminogen activator inhibitor type-1 (PAI-1), an established marker and mediator of cardiovascular risk, is produced extensively in adipose tissue. Fibrates are hypolipidemic peroxisome proliferator activated receptor-alpha (PPARalpha) agonists. Recent laboratory and clinical observations indicate that they are also anti-atherosclerotic. Mechanisms responsible, however, remain to be fully understood. The present study was designed to elucidate modulation of PAI-1 expression in adipose cells by fibrates as a potential mechanism. Expression of PPARalpha was verified by PCR, immunohistochemistry, and Western blotting. In cultured preadipocytes and adipocytes gemfibrozil and fenofibrate significantly reduced PAI-1 protein expression by up to 55 +/- 5% and 34 +/- 4% under basal conditions and up to 56 +/- 6% and 31 +/- 6% under conditions of stimulation of the cells with 40 pM transforming growth factor (TGF)beta, respectively. Quantification of mRNA showed that the gemfibrozil-induced effect was at least in part regulated at the transcriptional level. Incubations with non-fibrate PPARalpha agonists showed similar reductions in PAI-1 expression. The decrease in PAI-1 expression induced by gemfibrozil was inhibited by MK886, a PPARalpha inhibitor. Furthermore, preadipocytes isolated from PPARalpha-deficient mice produced significantly more PAI-1 than those from wild-type mice upon stimulation with TGFbeta. Finally, fenofibrate reduced PAI-1 expression both in plasma and adipose tissue of hyperlipidemic mice. Our data support the view that PPARalpha activation down-regulates PAI-expression in adipose cells that may contribute in part to the reduction in cardiovascular mortality seen with fibrates in clinical trials.
- Find related publications in this database (using NLM MeSH Indexing)
- Adipocytes - drug effects
- Adipocytes - metabolism
- Adipocytes - pathology
- Adipose Tissue - pathology
- Adult -
- Aged -
- Animals -
- Cells, Cultured -
- Female -
- Fenofibrate - pharmacology
- Gemfibrozil - pharmacology
- Gene Expression Regulation - drug effects
- Gene Expression Regulation - genetics
- Humans -
- Hypolipidemic Agents - pharmacology
- Mice -
- Mice, Inbred C57BL -
- Mice, Knockout -
- Middle Aged -
- PPAR alpha - genetics
- PPAR alpha - metabolism
- Plasminogen Activator Inhibitor 1 - genetics
- Plasminogen Activator Inhibitor 1 - metabolism
- Stem Cells - drug effects
- Stem Cells - metabolism
- Stem Cells - pathology
- Transforming Growth Factor beta - metabolism
- Find related publications in this database (Keywords)
- PAI-1
- adipocyte
- fibrate
- metabolic syndrome
- haemostasis