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

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 AT(1)-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 4GAG 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 muM losartan (p < 0.01), indicating an AT(1)-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. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.