Shear stress insensitivity of endothelial nitric oxide synthase expression as a genetic risk factor for coronary heart disease.
Coronary heart disease (CHD) is based on the development of atherosclerosis in coronary arteries. Shear stress-induced endothelial nitric oxide (NO) release not only contributes to local blood pressure control but also effectively helps to retard atherosclerosis. Therefore, functionally relevant polymorphisms in the endothelial NO synthase (NOS-3) gene may contribute to the development of CHD. NOS-3 expression was analyzed in endothelial cells isolated from umbilical cords genotyped for the -786C/T single nucleotide polymorphism (SNP) of the human nos-3 gene. Moreover, NO-dependent relaxation was examined in segments of saphenous vein isolated from genotyped patients undergoing aortocoronary bypass surgery, and patients subjected to quantitative coronary angiography were genotyped to verify an association between this SNP and CHD. Shear stress-induced NOS-3 mRNA and protein expression was present in TT and CT genotype cells but absent in cells with CC genotype. Pretreatment of these cells with a decoy oligonucleotide comprising position -800 to -779 of the C-type nos-3 promoter reconstituted shear stress-induced NOS-3 expression. These results were confirmed by reporter gene analysis with the corresponding nos-3 promoter luciferase constructs. In addition, the NO-mediated relaxant response of vein grafts from CC genotype patients was significantly attenuated as compared with the CT or TT genotype, and in CHD-positive patients, the CC genotype was significantly more frequent (19.0%) than in CHD-negative patients (4.4%). The -786C/T SNP of the nos-3 gene thus constitutes a genetic risk factor for CHD, presumably due to binding of an inhibitory transcription factor to the C-type promoter blocking shear stress-dependent maintenance of NOS-3 expression.
Cattaruzza
Marco
M
Department of Cardiovascular Physiology, University of Göttingen, Göttingen, Germany.
Guzik
Tomasz J
TJ
Słodowski
Wojciech
W
Pelvan
Ayşegül
A
Becker
Jürgen
J
Halle
Martin
M
Buchwald
Arnd B
AB
Channon
Keith M
KM
Hecker
Markus
M
D000328:Adult; D000483:Alleles; D002478:Cells, Cultured / Q000201:enzymology; D015331:Cohort Studies; D017023:Coronary Angiography; D001026:Coronary Artery Bypass; D003324:Coronary Artery Disease / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics; D004730:Endothelium, Vascular / Q000201:enzymology*; D004790:Enzyme Induction; D005260:Female; D005787:Gene Frequency; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D018056:Hemorheology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins / Q000502:physiology; D012307:Risk Factors; D012494:Sampling Studies; D012501:Saphenous Vein / Q000637:transplantation; D016037:Single-Blind Method; D013314:Stress, Mechanical; D014162:Transfection; D014470:Umbilical Cord; D014664:Vasodilation / Q000235:genetics
D009838:Oligodeoxyribonucleotides; D012333:RNA, Messenger; D012097:Repressor Proteins; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III