Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling.

Rudic, R. Daniel; Shesely, Edward G.; Maeda, Nobuyo; Smithies, Oliver; Segal, Steven S.; Sessa, William C.

doi:10.1172/jci1699

Cited by 756 publications

(567 citation statements)

References 38 publications

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“…Our findings are also in concordance with the observations in eNOS knockout mice, which have been found to have increased IMT. 41 In the present study, polymorphism in intron 4 of eNOS gene was not associated with carotid IMT. Conversely, Japanese investigators in haemodialysed patients found the odds ratio for carotid plaque was increased to 3.72 by the 4a allele of the intron 4 polymorphism.…”

Section: Discussionsupporting

confidence: 39%

Ambulatory blood pressure, left ventricular mass and vascular phenotypes in relation to the endothelial nitric oxide synthase gene Glu298Asp and intron 4 polymorphisms in a population-based family study

et al. 2005

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Reduced nitric oxide production is associated with pathological changes in the cardiovascular system. In a study of randomly chosen families, we analysed the relationship between two polymorphisms (Glu298Asp and intron 4) of the endothelial nitric oxide synthase (eNOS) and ambulatory blood pressure (ABP), left ventricular mass index (LVMI) and vascular phenotypes. The study population consisted of 127 parents and 167 offspring. All subjects underwent 24 h ABP monitoring using a SpaceLabs 90207 device. 2D and M-mode echocardiograms were obtained. Pulse wave velocity between the common carotid and femoral artery was measured with the Complior s device, and the carotid intima-media thickness (IMT) was assessed by ultrasound. For statistical analysis, covariables and correlations between relatives were taken into account. The frequency of genotypes was as follows: for Glu298Asp:55.1%-Glu/Glu, 40.1%-Glu/Asp and 4.8%-Asp/Asp; for intron 4: 65.0%-4 b/b, 33.3%-4 b/a and 1.7%-4 a/a, being in Hardy-Weinberg equilibrium (PX0.29). There was no relationship between the eNOS gene polymorphisms and ABP or LVMI either in parents or their offspring. Among parents, carriers of the 298Asp allele had higher IMT values as compared with Glu/Glu homozygotes (0.94 vs 0.70 mm; P ¼ 0.007). Among offspring, there was a similar tendency (0.60 vs 0.53 mm; P ¼ 0.10), which was confirmed by transmission disequilibrium tests for quantitative variables (PX0.07). Our findings indicate that the Glu298Asp polymorphism of eNOS identifies patients with larger carotid IMT, also in younger subjects.

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Section: Discussionsupporting

confidence: 39%

Ambulatory blood pressure, left ventricular mass and vascular phenotypes in relation to the endothelial nitric oxide synthase gene Glu298Asp and intron 4 polymorphisms in a population-based family study

et al. 2005

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“…6 A dysfunctional endothelium loses not only the capacity to regulate vascular tone, but also its anti-thrombotic and anti-aggregation properties for leukocytes and platelets. 7 Thromboxane A2, produced by the platelets, is the most important agent producing vasoconstriction, is increased in diabetics, and the smooth muscle of the vessels has a higher susceptibility to it.…”

Section: Pathogenesis Of Arterial Hypertension In Diabetesmentioning

confidence: 99%

Diabetes and hypertension physiopathology and therapeutics

et al. 2000

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Diabetes mellitus by itself, is a frequent and increasing public health problem. The prevalence in most Western countries varies between 2 to 5% and it is rapidly increasing in Asiatic countries due to changes in dietary habits during the last years. The association between diabetes mellitus and hypertension has been described in 60 to 65% of diabetics. In hypertension we find insulin resistance mainly in skeletal muscle involving the conversion of glucose to glycogen independently of blood flow. The degree of resistance is related to the severity of hypertension and varies between races. States of

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“…[1][2][3][4][5] Indeed, reduction of endothelial NO synthesis (endothelial dysfunction) predisposes the blood vessel to arteriosclerosis, [1][2][3][4][5] and the eNOS-deficient (eNOS-KO) mice exhibit accelerated vascular lesion formation. 6,7 As pharmacological tools to inhibit endothelial NO synthesis, synthetic L-arginine analogues have been used in vitro and in vivo. Among them, N -nitro-L-arginine methyl ester (L-NAME) is the most frequently used agent.…”

mentioning

confidence: 99%

Asymmetric Dimethylarginine Produces Vascular Lesions in Endothelial Nitric Oxide Synthase–Deficient Mice

Suda

Tsutsui

Morishita

et al. 2004

ATVB

174

124

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Objective-Asymmetric dimethylarginine (ADMA) is widely believed to be an endogenous nitric oxide synthase (eNOS) inhibitor. However, in this study, we examined our hypothesis that the long-term vascular effects of ADMA are not mediated by inhibition of endothelial NO synthesis. Methods and Results-ADMA was infused in wild-type and eNOS-knockout (KO) mice by osmotic minipump for 4 weeks. In wild-type mice, long-term treatment with ADMA caused significant coronary microvascular lesions. Importantly, in eNOS-KO mice, treatment with ADMA also caused an extent of coronary microvascular lesions that was comparable to that in wild-type mice. These vascular effects of ADMA were not prevented by supplementation of L-arginine, and vascular NO production was not reduced by ADMA treatment. Treatment with ADMA caused upregulation of angiotensin-converting enzyme (ACE) and an increase in superoxide production that were comparable in both strains and that were abolished by simultaneous treatment with temocapril (ACE inhibitor) or olmesartan (AT 1 receptor antagonist), which simultaneously suppressed vascular lesion formation. Key Words: asymmetric dimethylarginine Ⅲ arteriosclerosis Ⅲ nitric oxide Ⅲ endothelial nitric oxide synthase Ⅲ mice E ndothelium-derived nitric oxide (NO), synthesized from L-arginine by endothelial NO synthase (eNOS), has several important antiatherogenic actions. 1-5 Indeed, reduction of endothelial NO synthesis (endothelial dysfunction) predisposes the blood vessel to arteriosclerosis, 1-5 and the eNOS-deficient (eNOS-KO) mice exhibit accelerated vascular lesion formation. 6,7 As pharmacological tools to inhibit endothelial NO synthesis, synthetic L-arginine analogues have been used in vitro and in vivo. Among them, N -nitro-L-arginine methyl ester (L-NAME) is the most frequently used agent. [1][2][3][4][5] Long-term treatment with L-NAME is known to cause arteriosclerotic coronary lesions, especially at microvascular levels, in experimental animals. 8,9 This model with L-NAME is regarded as a useful animal model for examining the protective roles of endothelium-derived NO in the pathogenesis of arteriosclerosis. 8,9 See cover However, it is controversial whether these vascular effects of L-NAME are caused primarily by the inhibition of endothelial NO synthesis for the following reasons: first, the importance of endothelium-derived NO decreases as the vessel size becomes smaller, 10 whereas L-NAME-induced vascular lesions are prominent at microvascular levels; 8 second, long-term treatment with L-NAME does not reduce eNOS activity; 11 third, multiple actions of L-NAME other than simple inhibition of NO synthesis have been reported. 12,13 The most appropriate way to address this issue is to use mice that are deficient in the eNOS gene and to examine whether long-term treatment with L-NAME causes coronary vascular lesions in those mice. We have recently shown that treatment with L-NAME causes a comparable extent of Conclusions-These

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Direct evidence for the importance of endothelium-derived nitric oxide in vascular remodeling.

Cited by 756 publications

References 38 publications

Ambulatory blood pressure, left ventricular mass and vascular phenotypes in relation to the endothelial nitric oxide synthase gene Glu298Asp and intron 4 polymorphisms in a population-based family study

Ambulatory blood pressure, left ventricular mass and vascular phenotypes in relation to the endothelial nitric oxide synthase gene Glu298Asp and intron 4 polymorphisms in a population-based family study

Diabetes and hypertension physiopathology and therapeutics

Asymmetric Dimethylarginine Produces Vascular Lesions in Endothelial Nitric Oxide Synthase–Deficient Mice

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