Maternal iNOS genetic polymorphisms and hypertensive disorders of pregnancy

Amaral, Lorena M.; Palei, Ana C.; Sandrim, Valéria C.; Luizon, Marcelo R.; Cavalli, Ricardo de Carvalho; Duarte, Geraldo; Tanus‐Santos, José Eduardo

doi:10.1038/jhh.2011.65

Cited by 18 publications

(11 citation statements)

References 35 publications

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“…Although no previous study has examined the effects of iNOS inhibitors in pre-eclampsia models, iNOS upregulation has been implicated in both animal models and clinical hypertension [14,35,37]. In parallel with our findings, aminoguanidine (an iNOS inhibitor) decreased iNOS expression and lowered nitrotyrosine and superoxide levels in spontaneously hypertensive rats in association with suppression of hypertension development [14].…”

Section: Discussionsupporting

confidence: 87%

“…In conclusion, our findings clearly implicate iNOS in the hypertension associated with experimental pre-eclampsia. It is possible that iNOS inhibitors may be clinically useful in the therapy of pre-eclampsia, especially in particular groups of patients carrying specific iNOS gene variants associated with increased iNOS expression or activity, which have been found more frequently in patients with pre-eclampsia [37]. Further studies in patients are warranted to examine this possibility.…”

Section: Discussionmentioning

confidence: 99%

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Antihypertensive effects of inducible nitric oxide synthase inhibition in experimental pre‐eclampsia

Amaral

Pinheiro

Guimaraes

et al. 2013

J Cellular Molecular Medi

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Upregulation of inducible nitric oxide synthase (iNOS) has been reported in both experimental and clinical hypertension. However, although pro-inflammatory cytokines that up-regulate iNOS contribute to pre-eclampsia, no previous study has tested the hypothesis that a selective iNOS inhibitor (1400 W) could exert antihypertensive effects associated with decreased iNOS expression and nitrosative stress in pre-eclampsia. This study examined the effects of 1400 W in the reduced uteroplacental perfusion pressure (RUPP) placental ischaemia animal model and in normal pregnant rats. Sham-operated and RUPP rats were treated with daily vehicle or 1 mg/kg/day N-[3-(Aminomethyl) benzyl] acetamidine (1400 W) subcutaneously for 5 days. Plasma 8-isoprostane levels, aortic reactive oxygen species (ROS) levels and nicotinamide adenine dinucleotide phosphate (NADPH)-dependent ROS production were evaluated by ELISA, dihydroethidium fluorescence microscopy and lucigenin chemiluminescence respectively. Inducible nitric oxide synthase expression was assessed by western blotting analysis and aortic nitrotyrosine was evaluated by immunohistochemistry. Mean arterial blood pressure increased by ∼30 mmHg in RUPP rats, and 1400 W attenuated this increase by ∼50% (P < 0.05). While RUPP increased plasma 8-isoprostane levels, aortic ROS levels, and NADPH-dependent ROS production (P < 0.05), treatment with 1400 W blunted these alterations (P < 0.05). Moreover, while RUPP increased iNOS expression and aortic nitrotyrosine levels (P < 0.05), treatment with 1400 W blunted these alterations (P < 0.05). These results clearly implicate iNOS in the hypertension associated with RUPP. Our findings may suggest that iNOS inhibitors could be clinically useful in the therapy of pre-eclampsia, especially in particular groups of patients genetically more prone to express higher levels of iNOS. This issue deserves further confirmation.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Antihypertensive effects of inducible nitric oxide synthase inhibition in experimental pre‐eclampsia

Amaral

Pinheiro

Guimaraes

et al. 2013

J Cellular Molecular Medi

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“…1) [7–14]. Importantly, the only resolve for PE is delivery of placenta, leaving this disease one of the leading causes of preterm birth.…”

Section: Introductionmentioning

confidence: 99%

Pathophysiology and Current Clinical Management of Preeclampsia

et al. 2017

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Preeclampsia is characterized by blood pressure greater than 140/90 mmHg in the second half of pregnancy. This disease is a major contributor to preterm and low birth weight babies. The early delivery of the baby, which becomes necessary for maintaining maternal well-being, makes pre-eclampsia the leading cause for preterm labor and infant mortality and morbidity. Currently, there is no cure for this pregnancy disorder. The current clinical management of PE is hydralazine with labetalol and magnesium sulfate to slow disease progression and prevent maternal seizure, and hopefully prolong the pregnancy. This review will highlight factors implicated in the pathophysiology of preeclampsia and current treatments for the management of this disease.

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“…These findings are relevant because the search for genetic markers associated with HDP may allow early detection of those patients with increased susceptibility to these disease conditions, which are associated with increased morbidity and mortality. 39,40 In conclusion, although no significant genotype combinations were associated with GH, we found specific genotype combinations of MMP-9 and VEGF that are more (MMP-9-1562CC and VEGF-634CC, and combinations containing the MMP-9-1562CT genotype) or less common (MMP-9-1562CC and VEGF-634GG) in the PE group than in the NP group. Taken together, our results suggest an effect of these specific combinations on the genetic susceptibility of patients to PE.…”

Section: Discussionmentioning

confidence: 52%

Epistasis among eNOS, MMP-9 and VEGF maternal genotypes in hypertensive disorders of pregnancy

et al. 2012

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Polymorphisms of the endothelial nitric oxide synthase (eNOS), matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) genes were shown to be associated with hypertensive disorders of pregnancy. However, epistasis is suggested to be an important component of the genetic susceptibility to preeclampsia (PE). The aim of this study was to characterize the interactions among these genes in PE and gestational hypertension (GH). Seven clinically relevant polymorphisms of eNOS (T-786C, rs2070744, a variable number of tandem repeats in intron 4 and Glu298Asp, rs1799983), MMP-9 (C-1562T, rs3918242 and -90(CA) 13-25 , rs2234681) and VEGF (C-2578A, rs699947 and G-634C, rs2010963) were genotyped by TaqMan allelic discrimination assays or PCR and fragment separation by electrophoresis in 122 patients with PE, 107 patients with GH and a control group of 102 normotensive pregnant (NP) women. A robust multifactor dimensionality reduction analysis was used to characterize gene-gene interactions. Although no significant genotype combinations were observed for the comparison between the GH and NP groups (P40.05), the combination of MMP-9-1562CC with VEGF-634GG was more frequent in NP women than in women with PE (Po0.05). Moreover, the combination of MMP-9-1562CC with VEGF-634CC or MMP-9-1562CT with VEGF-634CC or-634GG was more frequent in women with PE than in NP women (Po0.05). These results are obscured when single polymorphisms in these genes are considered and suggest that specific genotype combinations of MMP-9 and VEGF contribute to PE susceptibility.

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Maternal iNOS genetic polymorphisms and hypertensive disorders of pregnancy

Cited by 18 publications

References 35 publications

Antihypertensive effects of inducible nitric oxide synthase inhibition in experimental pre‐eclampsia

Antihypertensive effects of inducible nitric oxide synthase inhibition in experimental pre‐eclampsia

Pathophysiology and Current Clinical Management of Preeclampsia

Epistasis among eNOS, MMP-9 and VEGF maternal genotypes in hypertensive disorders of pregnancy

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