[The influence of I/D polymorphism of the angiotensin I converting enzyme (ACE) gene and 4G/5G polymorphism of plasminogen activator inhibitor (PAI-1) gene promoter on the haemostatic system in patients with essential hypertension and dyslipidemia]

Abstract

Introduction: Many studies indicate that hypertension-related high shear stress and activation of renin-angiotensin-aldosterone (RAA) system lead to endothelium damage and imbalance among haemostatic factors secreted by this tissue. Tissue plasminogen activator (t-PA) and its inhibitor (PAI-1), von Willebrand factor (vWF), and soluble thrombomodulin (sTM) are haemostatic markers of endothelial injury related to hypertension. Hypertensive status is also accompanied by high fibrinogen (Fb) levels and blood platelet activation. The influence of RAA system on haemostatic disorders is mainly due to the action of angiotensin II (Ang II) on PAI-1 synthesis by endothelial cells. Ang II is generated by angiotensin converting enzyme (ACE). It is believed that genes encoding PAI-1 and ACE may interact and regulate the delicate balance in the haemostatic system. The aim of this study was to: (1) compare hypertensive and normotensive subjects with regard to haemostatic factors; (2) assess the effect of ACE I/D and PAI-1 4G/5G polymorphisms on haemostatic parameters in patients with essential hypertension as compared with normotensive subjects; (3) determine whether lipid disturbances modify the influence of ACE and PAI-1 gene polymorphisms on haemostatic factors; (4) investigate if there is an interaction of ACE and PAI-1 gene polymorphisms with haemostatic parameters in patients with essential hypertension.

Material and methods: 147 patients were enrolled in this study. They underwent a clinical and laboratory examination and were also interviewed. The patients were divided into two groups: hypertensive (HT-104 patients with untreated essential hypertension and without clinical signs of ischaemic heart disease); and normotensive (NT -43 healthy subjects). A subgroup of 45 patients diagnosed with mixed dyslipidemia was formed from the HT group. Haemostatic parameters (t-PA, PAI-1, Pbetathromboglobulin (PbetaTG), vWF, Fb) and ACE activity were determined using ELISA, ELFA, chronometric and spectrophotometric methods. Genotypes for ACE I/D and PAI-1 4G/5G polymorphisms were determined with the polymerase chain reaction amplification followed by electrophoresis of the product on an agarose gel and detection with ethidium bromide.

Conclusion: The results led to the following conclusions: (1) Untreated essential hypertension is associated with the prothrombotic state reflected by increased levels of fibrinogen and tissue plasminogen activator and its inhibitor; (2) Deletion alleles (D or 4G) potentiate the prothrombotic state manifested by fibrinolytic disturbances in hypertensive patients as compared with normotensive subjects; (3) Lipid disorders enhance the prothrombotic effect of deletion alleles (D or 4G) in untreated essential hypertension; (4) There is no interaction between ACE I/D and PAI-1 4G/5G polymorphisms in the regulation of levels of haemostatic factors.