ENDOTHELIUM DYSFUNCTION PATHWAY AND CAROTID INTIMA-MEDIA THICKNESS IN HYPERTENSIVE PATIENTS: ROLE OF NOS3 (RS2070744) AND GNB3 (RS5443) GENES’ POLYMORPHISMS

Abstract

Objective: The crucial function of endothelium’s regulatory mechanisms is to maintain the balance between Monoxide Nitrogen (NO) release and endothelium-derived contracting factors production. Therefore, it is prognostically important to clarify the endothelial function (EF) deterioration pathway through the early biomarkers of EF and carotid intima media thickness (IMT) changes depending on GNB3 (rs5443) and NOS3 (rs2070744) genes’ polymorphism in essential arterial hypertension (EAH). Design and method: One-hundred EAH patients with hypertensive-mediated organ damage (moderate-very high cardiovascular risks, aged 45–65 years) and 48 practically healthy (control) participated in the cohort case-control study. Soluble Vascular Cell Adhesion Molecule (sVCAM-1), total NO metabolites (NO2-/NO3-), transcriptional activity of NOS3 gene, Endothelium-Dependent Flow-Mediated Dilation of the Brachial Artery (FMD BA) and carotid IMT were studied. GNB3 (rs5443) and NOS3 (rs2070744) genotyping performed by TaqMan probes (CFx96ÔReal-Time PCR). Results: The connections of NOS3 (rs2070744) with decreased total NO metabolites (F = 71.11; p < 0.001), reduced NOS3 gene’s transcription activity (F = 8.71; p < 0.001) and sVCAM-1 increase (F = 6.96; p = 0.002) were found, especially in the C-allele carriers (particularly in CC-genotype patients with lower total NO metabolites value – by 16.46% and 40.88% (p < 0.001), lower transcription activity of NOS3 gene – 46.03% and 7 times (p < 0.001), higher sVCAM-1 – 35.48% and 89.48% (p < 0.001), respectively). ANOVA analysis didn’t confirm association of GNB3 (rs5443) gene with EF and carotid IMT. Severe EAH is associated with increased carotid IMT – 50.0% (p < 0.001) and 57.14% (p < 0.007), dilated carotid arteries – 17.36% (p = 0.012) and 21.79% (p = 0.004), decreased NOS3 gene’s transcription activity – 34.54% (p = 0.003). Severe structural carotid IMT changes in EAH patients (IMT > 0.9 mm) is followed by higher blood pressure values (p < 0.001), deterioration of EF: FMD BA decrease – 11.80% with compensatory increase of carotid arteries diameters – 17.38% and 21.99% (p < 0.001) and serum sVCAM-1 concentration – by 20.49% (p = 0.005). Conclusions: NOS3 (rs2070744), but not GNB3 (rs5443) gene associate with endothelial function impairment and carotid IMT in EAH patients.