Genetic variation and gender determine bradykinin type 1 receptor responses in human tissue: implications for the ACE-inhibitor-induced effects in patients with coronary artery disease

Abstract

The efficacy of the ACE (angiotensin-converting enzyme) inhibitor perindopril in coronary artery disease [EUROPA (European trial on reduction of cardiac events with perindopril in stable coronary artery disease) study] is associated with the rs12050217 A/G single nucleotide polymorphism in the B-1 receptor (bradykinin type 1 receptor) gene. To investigate the underlying mechanism, we examined the effect of this polymorphism on B-1-receptor-mediated coronary artery dilation and peripheral blood mononuclear cell activation. Vasorelaxant responses of human coronary microarteries from subjects without coronary disease to des-Arg(9)-bradykinin and to bradykinin were studied in organ bath experiments. Des-Arg(9)-bradykinin responses were endothelium-dependent and exclusively mediated by B-1 receptors, whereas responses to bradykinin were induced through B-2 receptors (bradykinin type 2 receptors). The presence of the G allele reduced the response to 3x10(-8) mol/l des-Arg(9)-bradykinin by 29% [AA (n = 13) compared with AG/GG (n = 8); P < 0.03], and tended to lower concentration-related responses (P = 0.065) to this agonist, whereas the responses to bradykinin were unaffected by the rs12050217 genotype. In freshly obtained human mononuclear cells 1 mu mol/l des-Arg(9)-bradykinin increased expression of the pro-inflammatory factors CXCL5 (CXC chemokine ligand 5) and IL6 (interleukin-6). These responses were not affected by genotype and exclusively occurred in blood cells from women, correlating (in the case of CXCL5) with their plasma 17 beta-oestradiol levels (r(2) = 0.32, P = 0.02; n=17). IL-1 beta (interleukin-1 beta) increased CXCL5 and IL6 expression in both genders, and this response was not associated with 17 beta-oestradiol levels. The gender difference in responses to B-1 receptor stimulation in blood mononuclear cells implies possible gender differences in the response to ACE inhibitor therapy, which needs to be studied more comprehensively. The observed decrease in coronary vasodilator response might contribute to the impaired treatment response to perindopril of G allele carriers found in the EUROPA study