A Promoter Polymorphism of the Endothelial Nitric Oxide Synthase Gene is Associated With Reduced mRNA and Protein Expression in Failing Human Myocardium

Abstract

Background Alterations of endothelial nitric oxide synthase (eNOS) enzyme activity via eNOS gene polymorphisms have been associated with significant cardiovascular morbidity and mortality. Both the thymidine to cytosine transition mutation (T−786→C) in the promoter region and the missense mutation in the exon 7 coding region of the eNOS gene (G894→T) have been associated with several cardiovascular disease states. We hypothesized that heart transplant recipients who carried at least one allele of either of the polymorphisms would have reduced myocardial tissue expression of eNOS measured in the explanted heart. Methods/Results Genomic DNA was isolated from myocardial tissue samples obtained from 43 explanted human hearts using standard methods. Regions of the eNOS gene were amplified from genomic DNA with a polymerase chain reaction using specific primers. Protein expression of eNOS was measured by Western blot analysis. There was a statistically significant decrease in mean eNOS expression in samples containing at least one allele for the T−786→C promoter polymorphism (p = 0.04) compared to patients homozygous for the T allele. There was no change in eNOS expression associated with the G894→T exonic polymorphisms. Conclusions: Our data show in failing human myocardium that the T−786→C promoter polymorphism is associated with reduced eNOS expression whereas the G894→T polymorphism of exon 7 is not associated with change in either eNOS mRNA or protein expression. Reduced eNOS expression associated with the promoter polymorphism may contribute to the vascular, contractile, and autonomic responses to ventricular failure.

The molecular and genetic aspects of adolescent girls anomalous uterine bleeding: the role of endothelial dysfunction syndrome

“…The relationship between existence of polymorphous allele C in 786T4C NOS3 gene and increased coronary arteries tone, altered reaction of coronary arteries on acetylcholine injection, was demonstrated in meta-analysis of 20 studies including 11 236 patients [12]. Therefore, polymorphous allele 786C of NOS3 gene in heterozygote and homozygote states (which was detected in LBW girls with AUB) is associated with endothelial dysfunction risk.…”

“…The study of endothelial NO synthase gene polymorphism reveals functionally interrelated polymorphisms 894 G/T (rs1799983) and 786 T/Q (rs2070744) [12]. The significant role of these polymorphisms demonstrated in cardiovascular diseases (ischemic heart disease, myocardial infarction, preeclampsia and stroke) and some other diseases (diabetes) [12,13].…”

T-786C variation in the promoter sequence of human <i>eNOS</i> gene markedly influences its expression level

“…A statistically significant decrease in average eNOS expression has been reported for the T-786C polymorphism and was suggested to contribute to the vascular, contractile, and autonomic responses in failing human myocardium (6). Another study provided evidence that the same SNP is associated with the presence and severity of angiographically defined CAD in the Italian population (7).…”

Genetic aspects of fetal programming of abnormal uterine bleeding in puberty: the role of endothelial disfunction

“…C. Lоcwood и соавт. [12,27] показали, что тканевая гипоксия, связанная с ингибированием активности кровотока в эндометрии и гиперпродукцией актив-ных форм кислорода при синдроме эндотелиальной дисфункции, увеличивает синтез ангиогенных фак-торов роста, таких как VEGF-A в HESC и ангиопоэ-тин-2 (Ang-2) в эндотелиальных клетках эндометрия, в то время как синтез ангиопоэтина-1 в HESC клет-ках уменьшается. В результате возрастает хрупкость сосудистой стенки, происходит активация некон-тролируемого ангиогенеза в эндометрии, что влечет за собой развитие АМК.…”

“…Поэтому логично предположить, что девочки, рож-денные с СЗРП от матерей, у которых беременность протекала на фоне синдрома эндотелиальной дис-функции с исходом в преэклампсию и фетоплацен-тарную недостаточность, унаследовали определен-ный полиморфизм генов, регулирующих функцию эндотелиальной системы. Фенотипически эндоте-лиальная дисфункция у этих девочек может реализо-ваться в развитие аномальных маточных кровотече-ний пубертатного периода, связанных с нарушением баланса тканевых эндотелиальных факторов, сосу-дистого тонуса, ангиогенеза и локального гемостаза в эндометрии [12,13].…”