Genetic polymorphisms G894T on the eNOS gene is associated with endothelial function and vWF levels in premature myocardial infarction survivors Charalambos Antoniades, Dimitris Tousoulis * , Carmen Vasiliadou, Christos Pitsavos, Marina Toutouza, Costas Tentolouris, Kyriakoula Marinou, Christodoulos Stefanadis Athens University Medical School, A’ Cardiology Department, Hippokration Hospital, S. Karagiorga street 69, 166 75, Glifada, Athens, Greece Received 4 December 2004; received in revised form 23 February 2005; accepted 27 February 2005 Available online 22 April 2005 Abstract Background: Genetic polymorphism G894T on endothelial nitric oxide synthase (eNOS) gene has been associated with endothelial dysfunction in young smokers, but its role in the pathogenesis of MI is obscure. We examined the effect of G894T polymorphism on endothelial function, on markers of endothelial cells injury and activation such as von Willebrand factor (vWF) and on serum levels of proinflammatory cytokines such as interleukins 6 (IL-6) and 1b (IL-1b), in young myocardial infarction (MI) survivors. Methods: The study population consisted of 56 patients with a history of premature MI. The forearm blood flow (FBF) was measured by using strain-gauge plethysmography during reactive hyperemia and after sublingual administration of nitroglycerin. G894T polymorphism was determined by polymerase chain reaction (PCR), while plasma vWF and serum IL1b and IL-6 levels were determined with ELISA. Results: There was no significant difference in resting FBF and in the responses to nitroglycerin between the genotypes. However, the presence of T allele (GT + TT, n = 35) was associated with decreased FBF during reactive hyperemia (10.23 T 0.70 ml/100ml tissue/min) and decreased forearm vasodilatory response to reactive hyperemia (54.28 T 4.81%) compared to GG (13.82 T 0.92 ml/100 ml tissue/min and 83.92 T 9.89% respectively, p < 0.01 for both). Carriers of the T allele had also higher levels of vWF (79.66 T 5.56%) compared to GG (60.94 T 5.27% p < 0.05). However, no significant difference was observed in IL-1b and IL-6 serum levels between the genotypes ( p = ns for both). Conclusions: The presence of 894T allele on eNOS gene is associated with impaired endothelial function and higher levels of von Willebrand factor in relatively young patients with myocardial infarction. This finding implies that genetic polymorphism G894T on eNOS may affect endothelial function in patients with a history of premature myocardial infarction. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Endothelial function; Endothelial nitric oxide synthase; Polymorphisms; Thrombosis 1. Introduction Nitric oxide (NO) produced in endothelial cells by endothelial nitric oxide synthase (eNOS) plays a pivotal role in vascular homeostasis by regulating vascular tone and endothelial – leukocyte interactions [1]. Furthermore, NO maintains endothelial integrity, having also antithrombotic, anti-inflammatory and antioxidant properties [1]. Genetic polymorphism G894T on eNOS gene, leads to a 298 Glu/ Asp substitution on eNOS molecule, but it is unclear whether it affects NO synthesis [2]. There is clinical evidence that G894T may affect the development of myocardial infarction (MI) since it has been associated with coronary spasm [3,4] and higher risk for coronary artery disease and MI [5–7], although its actual role has been questioned by several studies [8–10]. Endothelial dysfunction is accompanied by increased plasma levels of von Willebrand factor (vWF), a molecule 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.02.039 * Corresponding author. Tel.: +30 210 7782466; fax: +30 210 7485039. E-mail address: tousouli@med.uoa.gr (D. Tousoulis). International Journal of Cardiology 107 (2006) 95 – 100 www.elsevier.com/locate/ijcard