<i>eNOS</i> 894T allele and coronary blood flow at rest and during adenosine-induced hyperemia

Naber, Christoph; Baumgart, Dietrich; Altmann, Christoph; Siffert, Winfried; Erbel, Raimund; Heusch, Gerd

doi:10.1152/ajpheart.2001.281.5.h1908

Cited by 54 publications

(43 citation statements)

References 23 publications

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“…57,58 Individuals homozygous for the Asp298 allele have also been shown to exhibit a reduced blood pressure fall after exercise training 61 and to have lower basal blood flow and reduced vasodilation to adenosine in their coronary arteries. 62 In addition, they have an enhanced systemic pressor response to phenylephrine 63 and a reduced flow-mediated dilatation of the brachial artery. 59 These findings suggest that subjects homozygous for the Asp298 allele generate low NO in vivo and may be more susceptible to endothelial dysfunction, which might account for the increased risk of IHD.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Nitric Oxide Synthase Genotype and Ischemic Heart Disease

Casas¹,

Bautista²,

Humphries³

et al. 2004

Circulation

276

168

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Background-Polymorphisms in the endothelial nitric oxide synthase (eNOS) gene may influence the risk of ischemic heart disease (IHD), but data from published studies with individually low statistical power are conflicting. To evaluate the role of polymorphisms in the eNOS gene in IHD, we considered all available studies in a meta-analysis. Methods and Results-Case-control studies evaluating the association between the Glu298Asp, Ϫ786TϾC, and intron-4 polymorphisms and IHD were searched in MEDLINE and EMBASE up to January 2003. The principal prior hypothesis was that homozygosity for eNOS Asp298, the Ϫ786C allele in the promoter, or the intron-4 (a allele) would be associated with an increased risk of IHD. Data were available for 9867 cases and 13 161 controls from 26 studies. Homozygosity for the Asp298 was associated with an increased risk of IHD (OR, 1.31; 95% CI, 1.13 to 1.51). Although there was significant heterogeneity among studies of Asp298 (P Het ϭ0.0002), which was largely accounted for by a single study, the increase in risk was still significant after exclusion of that study from analysis. Homozygosity for the intron-4a allele was also significantly associated with higher risk of IHD (OR, 1.34; 95% CI, 1.03 to 1.75). However, no significant association was found with the Ϫ786C allele (OR, 1.06; 95% CI, 0.89, 1.25). Conclusions-Individuals homozygous for the Asp298 and intron-4a alleles of eNOS are at moderately increased risk of IHD. These findings support the proposal that common genetic variations in the eNOS gene contribute to atherosclerosis susceptibility, presumably by effects on endothelial NO availability.

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Section: Discussionmentioning

confidence: 99%

Endothelial Nitric Oxide Synthase Genotype and Ischemic Heart Disease

Casas¹,

Bautista²,

Humphries³

et al. 2004

Circulation

276

168

View full text Add to dashboard Cite

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“…Among the identified eNOS polymorphisms, the G894T substitution within exon 7 resulting in the conversion of glutamate to aspartate at position 298 (Glu298Asp variant) is the one most frequently studied and has been reported to be associated with atherosclerotic coronary artery disease in two independent cohorts recruited from the Cambridge Heart AntiOxidant Studies (CHAOS-I and CHAOS-II). 13 The Glu298Asp variant was also reported to be associated with an enhanced systemic pressor response to phenylephrine in a French cohort, 14 a lower basal blood flow but a preserved response to adenosine in coronary arteries in Caucasians of German descent 15 and vasospastic angina pectoris in a Japanese population, 16 as well as with essential hypertension resistant to conventional antihypertensive therapy. 17 While these studies showed association of the Glu298Asp variant with atherosclerotic coronary artery disease, other studies do not support these findings.…”

Section: Enos Gene Expression In Atherosclerosis Enos Gene Polymorphimentioning

confidence: 98%

Recent Advances in Understanding Endothelial Dysfunction in Atherosclerosis

Yang

Ming²

2006

Clinical Medicine & Research

178

117

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Over the last two decades, it has become evident that decreased bioavailability of endothelial nitric oxide (NO) produced from endothelial NO synthase (eNOS), referred to as endothelial dysfunction, plays a crucial role in the development and progression of atherosclerosis. Much progress has been made in understanding the mechanisms of decreased endothelial NO bioavailability at the levels of regulation of eNOS gene expression, eNOS enzymatic activity and NO inactivation. Initial studies suggest that increasing eNOS gene expression would improve endothelial NO release in the hope of inhibiting the progression of atherosclerosis. Recent experimental studies, however, do not always support this therapeutic concept and show some evidence that overexpression of eNOS in atherosclerosis may be even harmful for the disease progression.Thus, recent research to improve endothelial function in atherosclerosis has focused on regulation of eNOS enzymatic activity and prevention of NO inactivation by oxidative stress. Since the role of oxidative stress in endothelial NO bioavailability has been reviewed in a large number of comprehensive articles, this article focuses on the relevant regulatory mechanisms of eNOS enzymatic activity that are emerging to play a role in endothelial dysfunction in atherosclerosis.

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“…101 Although eNOS polymorphisms and altered coronary eNOS expression are associated with hypertension, 96,98,99 little direct evidence links mutations in the eNOS gene to specific mechanisms of coronary vascular dysfunction in hypertension. Certain polymorphisms for the 27 bp repeat at intron 4 and for the G894T have been associated with alterations in coronary vasomotor responses, 102,103 but this has not been assessed in a manner that allows for conclusions regarding the endothelium, or NO-dependency of the response. Thus, the precise mechanisms by which eNOS polymorphisms might affect coronary vascular function in hypertension have not yet been well established, and this important issue remains to be elucidated experimentally.…”

Section: Enos Polymorphisms Associated With Hypertension and Coronarymentioning

confidence: 99%

Nitric oxide and coronary vascular endothelium adaptations in hypertension

Levy

Chung²,

Kroetsch

et al. 2009

VHRM

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This review highlights a number of nitric oxide (NO)-related mechanisms that contribute to coronary vascular function and that are likely affected by hypertension and thus become important clinically as potential considerations in prevention, diagnosis, and treatment of coronary complications of hypertension. Coronary vascular resistance is elevated in hypertension in part due to impaired endothelium-dependent function of coronary arteries. Several lines of evidence suggest that other NO synthase isoforms and dilators other than NO may compensate for impairments in endothelial NO synthase (eNOS) to protect coronary artery function, and that NO-dependent function of coronary blood vessels depends on the position of the vessel in the vascular tree. Adaptations in NOS isoforms in the coronary circulation to hypertension are not well described so the compensatory relationship between these and eNOS in hypertensive vessels is not clear. It is important to understand potential functional consequences of these adaptations as they will impact the efficacy of treatments designed to control hypertension and coronary vascular disease. Polymorphisms of the eNOS gene result in significant associations with incidence of hypertension, although mechanistic details linking the polymorphisms with alterations in coronary vasomotor responses and adaptations to hypertension are not established. This understanding should be developed in order to better predict those individuals at the highest risk for coronary vascular complications of hypertension. Greater endothelium-dependent dilation observed in female coronary arteries is likely related to endothelial Ca 2+ control and eNOS expression and activity. In hypertension models, the coronary vasculature has not been studied extensively to establish mechanisms for sex differences in NO-dependent function. Genomic and nongenomic effects of estrogen on eNOS and direct and indirect antioxidant activities of estrogen are discussed as potential mechanisms of interest in coronary circulation that could have implications for sex-and estrogen status-dependent therapy for hypertension and coronary dysfunction. The current review identifies some important basic knowledge gaps and speculates on the potential clinical relevance of hypertension adaptations in factors regulating coronary NO function.

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eNOS 894T allele and coronary blood flow at rest and during adenosine-induced hyperemia

Cited by 54 publications

References 23 publications

Endothelial Nitric Oxide Synthase Genotype and Ischemic Heart Disease

Endothelial Nitric Oxide Synthase Genotype and Ischemic Heart Disease

Recent Advances in Understanding Endothelial Dysfunction in Atherosclerosis

Nitric oxide and coronary vascular endothelium adaptations in hypertension

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