Polymorphism of Angiotensin Converting Enzyme Gene Is Associated With Circulating Levels of Plasminogen Activator Inhibitor-1

Abstract

The deletion (D) allele of the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene is strongly associated with an increased level of circulating ACE. The ACE gene polymorphism may influence the production of angiotensin II (Ang II). It has been shown that Ang II modulates fibrinolysis, that is, Ang II increases plasminogen activator inhibitor-1 (PAI-1) mRNA and plasma PAI-1 levels in vitro and in vivo. Considered together, we tested the hypothesis that the deletion allele of the ACE gene might be associated with increased levels of PAI-1. We related the ACE genotype to PAI-1 antigen levels in 603 men and 221 women attending a routine health screening. As a whole, the plasma PAI-1 level was not strongly associated with ACE genotype. Since the PAI-1 level was significantly influenced by well-known risk factors for coronary artery disease (CAD), we further analyzed the data after excluding subjects with major cardiovascular risk factors. In low-risk male subjects, the DD genotype had significantly higher levels of plasma PAI-1 (DD: 20.3 +/- 2.2; DI: 13.9 +/- 1.1; II: 13.6 +/- 1.3 ng/mL, P = .010 by ANOVA). In low-risk female subjects, the DD genotype showed a tendency to a high level of plasma PAI-1 without statistical significance. When analysis was restricted to postmenopausal women (age > or = 55 or FSH > or = 35 ng/mL), the DD genotype showed a significantly higher level of PAI-1 than subjects with the DI and II genotypes (27.7 +/- 6.2 versus 15.6 +/- 1.8 ng/mL, P = .028). The DD polymorphism of the ACE gene is associated with high PAI-1 levels in male and possibly in postmenopausal female subjects who have lower conventional cardiovascular risk factors. These results suggest that the increased ACE activity caused by DD polymorphism may play an important role in elevating the level of plasma PAI-1. Our data support the notion that the genetic variation of ACE contributes to the balance of the fibrinolytic pathway.

Association of hypertensive status and its drug treatment with lipid and haemostatic factors in middle-aged men: the PRIME Study

“…9,10,[34][35][36] Several experimental studies have shown that PAI-1 activity is stimulated by angiotensin II, or associated with ACE gene polymorphism, 37 although this latter association has been questioned by others. 38 Thus, antihypertensive drugs acting within the renin-angiotensin system should also exert effects within the fibrinolytic system.…”

Type 2 Diabetes and Fibrinolysis

“…On the contrary insulin inhibits synthesis of PAI-1 in the endothelium induced by TGF-, probably due to activated cGMP and cAMP systems. Insulin along with leptin also stimulates the PAI-1 production in vascular smooth muscles (Eriksson et al, 1998;Hamsten & Eriksson, 1994;Kawai et al, 1996;Kim et al, 1997;Li et al, 1997;Peiretti et al, 1997;Vaughan, 1997Vaughan, , 2005Yamauchi et al, 1997).…”

The Presence of PAI-1 4G/5G and ACE DD Genotypes Increases the Risk of Early-Stage AVF Thrombosis in Hemodialysis Patients

“…16 The studies in the literature on this subject are contradictory. In this study, we investigated the effects of ACE gene polymorphism, thrombophilic factor gene polymorphisms, and homocysteine level on AVF function in HD patients.…”