Relationship between the G894T polymorphism (Glu 298 Asp variant) in endothelial nitric oxide synthase and nitric oxide-mediated endothelial function in human atherosclerosis

被引:60
作者
Guzik, TJ
Black, E
West, NEJ
McDonald, D
Ratnatunga, C
Pillai, R
Channon, KM [1 ]
机构
[1] John Radcliffe Hosp, Dept Cardiovasc Med, John Radcliffe Hosp, Oxford OX3 9DU, England
[2] John Radcliffe Hosp, Dept Cardiothorac Surg, John Radcliffe Hosp, Oxford OX3 9DU, England
来源
AMERICAN JOURNAL OF MEDICAL GENETICS | 2001年 / 100卷 / 02期
关键词
atherosclerosis; endothelium; genetics; nitric oxide synthase; polymorphism;
D O I
10.1002/ajmg.1229
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Nitric oxide (NO), produced by endothelial nitric oxide synthase (eNOS), plays important roles in normal vascular homeostasis, and reduced endothelial NO bioactivity is an important feature of vascular disease states. The Glu298Asp (G894T) polymorphic variant of eNOS has been associated with vascular disease, but functional data are lacking. Accordingly, we examined the relationships between NO-mediated endothelial function, the presence of the eNOS Glu298Asp variant, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations to different agonists were determined in human saphenous veins obtained from patients with coronary artery disease and identified risk factors (n = 104), Patients were genotyped for the eNOS G894T polymorphism. Nitric oxide-mediated endothelial vasorelaxations were highly variable between patients. Reduced vasorelaxations were associated with increased number of clinical risk factors for atherosclerosis (r = - 0.54, P < 0.001), whereas the Glu298Asp variant was not associated with any differences in contractions to phenylephrine, NO-mediated vasorelaxations to acetylcholine, bradykinin or calcium ionophore, or relaxations to the NO donor sodium nitroprusside. Increased atherosclerotic risk factors, but not the presence of the eNOS Glu298Asp variant, are associated with impaired nitric oxide-mediated endothelial vasomotor function, suggesting that this polymorphism does not have a major direct functional effect on vascular eNOS activity in human atherosclerosis. <(c)> 2001 Wiley-Liss, Inc.
引用
收藏
页码:130 / 137
页数:8
相关论文
共 32 条
[1]   LACK OF EVIDENCE FOR LINKAGE OF THE ENDOTHELIAL-CELL NITRIC-OXIDE SYNTHASE GENE TO ESSENTIAL-HYPERTENSION [J].
BONNARDEAUX, A ;
NADAUD, S ;
CHARRU, A ;
JEUNEMAITRE, X ;
CORVOL, P ;
SOUBRIER, F .
CIRCULATION, 1995, 91 (01) :96-102
[2]   In vivo gene transfer of nitric oxide synthase enhances vasomotor function in carotid arteries from normal and cholesterol-fed rabbits [J].
Channon, KM ;
Qian, HS ;
Neplioueva, V ;
Blazing, MA ;
Olmez, E ;
Shetty, GA ;
Youngblood, SA ;
Pawloski, J ;
McMahon, T ;
Stamler, JS ;
George, SE .
CIRCULATION, 1998, 98 (18) :1905-1911
[3]   Nitric oxide synthase in atherosclerosis and vascular injury - Insights from experimental gene therapy [J].
Channon, KM ;
Qian, H ;
George, SE .
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2000, 20 (08) :1873-1881
[4]   Nitric oxide synthase: Role in the genesis of vascular disease [J].
Cooke, JP ;
Dzau, VJ .
ANNUAL REVIEW OF MEDICINE, 1997, 48 :489-509
[5]   Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase [J].
Feron, O ;
Dessy, C ;
Moniotte, S ;
Desager, JP ;
Balligand, JL .
JOURNAL OF CLINICAL INVESTIGATION, 1999, 103 (06) :897-905
[6]   Structural characterization of nitric oxide synthase isoforms reveals striking active-site conservation [J].
Fischmann, TO ;
Hruza, A ;
Niu, XD ;
Fossetta, JD ;
Lunn, CA ;
Dolphin, E ;
Prongay, AJ ;
Reichert, P ;
Lundell, DJ ;
Narula, SK ;
Weber, PC .
NATURE STRUCTURAL BIOLOGY, 1999, 6 (03) :233-242
[7]   Ca2+-independent activation of the endothelial nitric oxide synthase in response to tyrosine phosphatase inhibitors and fluid shear stress [J].
Fleming, I ;
Bauersachs, J ;
Fisslthaler, B ;
Busse, R .
CIRCULATION RESEARCH, 1998, 82 (06) :686-695
[8]   Cellular and molecular mechanisms of endothelial cell dysfunction [J].
Harrison, DG .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 100 (09) :2153-2157
[9]   Endothelial nitric oxide synthase gene polymorphism and acute myocardial infarction [J].
Hibi, K ;
Ishigami, T ;
Tamura, K ;
Mizushima, S ;
Nyui, N ;
Fujita, T ;
Ochiai, H ;
Kosuge, M ;
Watanabe, Y ;
Yoshii, Y ;
Kihara, M ;
Kimura, K ;
Ishii, M ;
Umemura, S .
HYPERTENSION, 1998, 32 (03) :521-526
[10]   A common variant of the endothelial nitric oxide synthase (Glu298→Asp) is a major risk factor for coronary artery disease in the UK [J].
Hingorani, AD ;
Liang, CF ;
Fatibene, J ;
Lyon, A ;
Monteith, S ;
Parsons, A ;
Haydock, S ;
Hopper, RV ;
Stephens, NG ;
O'Shaughnessy, KM ;
Brown, MJ .
CIRCULATION, 1999, 100 (14) :1515-1520