Acidic Hydrolysis as a Mechanism for the Cleavage of the Glu298 → Asp Variant of Human Endothelial Nitric-oxide Synthase

Fairchild, Todd A.; Fulton, David; Fontana, Jason; Gratton, Jean‐Philippe; McCabe, Timothy J.; Sessa, William C.

doi:10.1074/jbc.m103647200

Cited by 153 publications

(108 citation statements)

References 30 publications

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“…Failure of this adaptation is thought to result in increased blood pressure, proteinuria, and wide-spread endothelial dysfunction (classical pre-eclampsia), arteriolar contraction, ischaemia of the decidua basalis, necrosis and haemorrhage (classical placental abruption). Although reduced NO bio-availability has already been reported in eNOS Asp298 homozygous individuals, there remains controversy about the interpretation of these findings (Fairchild et al 2001;Noiri et al 2002;Serrano et al 2004).…”

Section: Discussionmentioning

confidence: 85%

The Glu298Asp variant of the endothelial nitric oxide synthase gene is associated with an increased risk for abruptio placentae in pre-eclampsia

2005

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Attempts to define a pre-eclampsia susceptibility profile have been hampered by the wide clinical spectrum of the condition and the complex genetics underlying it. Genes that modulate blood pressure, fluid homeostasis and placental vascular development have been considered plausible candidates. Among these are the angiotensinogen (AGT) gene variant Met235Threo, which has been associated with pre-eclampsia and the endothelial nitric oxide synthase (eNOS) polymorphism Glu298Asp, which has been associated with both preeclampsia and abruptio placentae, a condition that often co-exists with pre-eclampsia. The aim of this study was to investigate a potential association between these gene variants and pre-eclampsia with and without abruptio placentae in a South African patient group. Fifty primigravidas with early onset, severe pre-eclampsia, 50 women presenting primarily with abruptio placentae (whether associated with pre-eclampsia or not) and a control panel of 50 healthy pregnant women constituted the study groups. The Met235Threo and Glu298Asp variants were characterised by polymerase chain reaction and restriction enzyme analysis. No association was demonstrated between the M235T variant of the AGT gene and pre-eclampsia or abruptio placentae. In contrast, the combined frequency of the eNOS variant genotypes (GT and TT) was significantly higher in the abruptio placentae group (49%) than the control group (21%) (p=0.006). Furthermore, in the pre-eclampsia patients who subsequently developed abruptio placentae, the eNOS GT genotype emerged as a major risk factor for the development of abruptio placentae (p<0.0001). These data suggest that the presence of a Glu298Asp eNOS variant may pre-dispose a preeclamptic woman to develop abruptio placentae or that it is a marker for predisposition.

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Section: Discussionmentioning

confidence: 85%

The Glu298Asp variant of the endothelial nitric oxide synthase gene is associated with an increased risk for abruptio placentae in pre-eclampsia

2005

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“…Two recent studies have shown that eNOS Asp298 is subject to selective proteolytic cleavage in endothelial cells and vascular tissues, and this could account for reduced vascular NO generation in subjects homozygous for this variant, 30,31 although these findings have been debated. 32 The findings from molecular studies have received some support from physiological stud- …”

Section: Discussionmentioning

confidence: 99%

Endothelial NO Synthase Genotype and Risk of Preeclampsia

et al. 2004

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Abstract-Polymorphisms in the endothelial NO synthase (eNOS) gene have been evaluated as risk factors for preeclampsia. However, data from small studies are conflicting. We assessed whether eNOS genotypes alter the risk of preeclampsia in a population in which the incidence of this disorder is high. A total of 844 young pregnant women (322 preeclamptic and 522 controls) were recruited from 5 cities. Genotyping for the Glu298Asp, intron-4 and -786T3 C polymorphisms in the eNOS gene was conducted.

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“…The few functional studies that have been attempted for the E298D and intron 4 VNTR variants, as well as the results of other clinical association studies, have been discordant. 13,14 Therefore, the results of the present study should be interpreted with caution and considered provisional pending confirmation in additional studies and evidence of supportive functional data.…”

Section: See P 826mentioning

confidence: 99%