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Cardiovascular Research 2004 63(1):176-185; doi:10.1016/j.cardiores.2004.03.023
© 2004 by European Society of Cardiology
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Copyright © 2004, European Society of Cardiology

Influence of the 4G/5G PAI-1 genotype on angiotensin II-stimulated human endothelial cells and in patients with hypertension

C Roncala,b, J Orbea,b, J.A Rodrigueza,b, M Belzuncea,b, O Beloquic, J Diezb and J.A Páramo*,a,b

aAtherosclerosis Research Laboratory, School of Medicine, University of Navarra, 31080-Pamplona, Spain
bDivision of Cardiovascular Pathophysiology, Foundation for Applied Medical Research (FIMA), School of Medicine, University of Navarra, Pamplona, Spain
cUniversity Hospital, University of Navarra, Pamplona, Spain

*Corresponding author. Atherosclerosis Research Laboratory, School of Medicine, University of Navarra, 31080-Pamplona, Spain. Tel.: +34-948296397; fax: +34-948296500. Email address: japaramo{at}unav.es

Background: We examined the influence of the 4G/5G PAI-1 (plasminogen activator inhibitor) genotype on Angiotensin II (Ang II)-induced PAI-1 expression by human endothelial cells (HUVEC) in the presence and absence of AT1-receptor blocker losartan, and screened for this polymorphism in relation to plasma PAI-1 and arterial pressure in apparently healthy subjects. Methods and results: Genotyped cultured HUVEC were incubated with Ang II (10–8 M) with or without losartan up to 24 h. PAI-1 mRNA was determined in cell extracts and protein and activity assessed in supernatants and extracellular matrix (ECM). Ang II increased PAI-1 mRNA and activity in a genotype-dependent manner, higher values observed for 4G/4G HUVEC compared with 4G/5G and 5G/5G genotypes (p<0.05). Laser confocal microscopy and Western blot analysis showed increased PAI-1 protein within ECM in Ang II-stimulated cultures. PAI-1 expression and protein secretion induced by Ang II in 4G/4G HUVEC was completely inhibited by preincubation with 0.05 µM losartan (p<0.01), indicating an AT1-mediated effect. In a group of hypertensives homozygous for the 4G allele, PAI-1 antigen was significantly increased (51.0±10.1 ng/ml) compared with normotensives (28.3±4.0 ng/ml) and hypertensives carrying the 5G allele (p<0.05). Conclusions: The 4G/5G PAI-1 polymorphism determines the endothelial PAI-1 upregulation by Ang II and the inhibitory response to losartan. Analysis of PAI-1 genotypes may help identifying subgroups of hypertensives at higher cardiovascular risk.

KEYWORDS PAI-1; Atherosclerosis; Polymorphism; Endothelium; Angiotensin-II; Arterial hypertension

Time for primary review 28 days


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