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|The 4G/5G PAI-1 polymorphism influences the endothelial response to IL-1 and the modulatory effect of pravastatin|
|Authors: ||Roncal, C. (Carmen)|
Orbe, J. (Josune)
Belzunce, M. (M.)
Rodriguez, J.A. (José Antonio)
Paramo, J.A. (José Antonio)
Plasminogen activator inhibitor-1
|Issue Date: ||2006|
|Publisher version: ||http://bit.ly/LfWwiJ|
|Citation: ||Roncal C, Orbe J, Belzunce M, Rodriguez JA, Paramo JA. The 4G/5G PAI-1 polymorphism influences the endothelial response to IL-1 and the modulatory effect of pravastatin. J Thromb Haemost 2006 Aug;4(8):1798-1803.|
BACKGROUND: Increased plasminogen activator inhibitor (PAI-1) levels lead to impaired fibrinolytic function associated with higher cardiovascular risk. PAI-1 expression may be regulated by different inflammatory cytokines such as interleukin-1alpha (IL-1). Several polymorphisms have been described in the PAI-1 gene.
AIM: We examined the influence of the 4G/5G polymorphism in the promoter region on IL-1alpha-induced PAI-1 expression by human umbilical vein endothelial cells (HUVEC) in presence or absence of pravastatin.
METHODS AND RESULTS: Genotyped HUVEC were incubated with IL-1alpha (500 U mL(-1)) in presence or absence of pravastatin (1-10 microm). PAI-1 expression was analyzed by real time polymerase chain reaction (PCR), and PAI-1 antigen measured in supernatants by ELISA. IL-1alpha increased PAI-1 secretion in a genotype-dependent manner, and higher values were observed for 4G/4G compared with both 4G/5G and 5G/5G cultures (P < 0.05). Preincubation of HUVEC with 10 microm pravastatin significantly reduced IL-1-induced PAI-1 expression in 4G/4G HUVEC compared with untreated cultures (177.5% +/- 24.5% vs. 257.9% +/- 39.0%, P < 0.05). Pravastatin also attenuated the amount of secreted PAI-1 by 4G/4G HUVEC after IL-1 stimulation (5020.6 +/- 165.7 ng mL(-1) vs. 4261.1 +/- 309.8 ng mL(-1), P < 0.05). This effect was prevented by coincubation with mevalonate, indicating a dependence on HMG-CoA reductase inhibition.
CONCLUSIONS: The endothelial 4G/5G PAI-1 genotype influences the PAI-1 response to IL-1alpha and the modulatory effect of pravastatin. As increased PAI-1 levels have been linked to cardiovascular disease the observed endothelial modulation by pravastatin may have potential clinical implications.
|Permanent link: ||http://hdl.handle.net/10171/22248|
|Appears in Collections:||DA - CIMA - Cardiovasculares - Aterosclerosis e inflamación - Artículos de revista|
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