The A376G(A+) variant of the glucose-6-phosphate dehydrogenase gene is associated with endothelial dysfunction in African Americans

Forgione, Marc A.; Loscalzo, Joseph; Holbrook, Monika; Melduni, Rowlens M.; Palmisano, Joseph; Maxwell, C. Mervyn; Baldwin, Clinton; Vita, Joseph A.

doi:10.1016/s0735-1097(03)81741-2

Cited by 8 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings correlate with observations made in a preliminary clinical study that investigated brachial artery vascular reactivity in G6PD-deficient patients. In this study, 18 healthy G6PDdeficient African-American subjects with the A326G mutation were found to have impaired flow-mediated dilation 38 . While the goal of our study was to examine the effects of aldosterone on G6pd activity in the vascular endothelium, we have previously demonstrated that vascular smooth muscle cells with deficient G6pd activity have increased ROS accumulation 39 .…”

Section: Discussionmentioning

confidence: 79%

Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity

Leopold

Dam

Maron

et al. 2007

Nat Med

Self Cite

312

259

View full text Add to dashboard Cite

Hyperaldosteronism is associated with impaired vascular reactivity; however, the mechanisms by which aldosterone promotes endothelial dysfunction remain unknown. Glucose-6-phosphate dehydrogenase (G6PD) modulates vascular function by limiting oxidant stress to preserve bioavailable nitric oxide (NO(*)). Here we show that aldosterone (10(-9)-;10(-7) mol/l) decreased endothelial G6PD expression and activity in vitro, resulting in increased oxidant stress and decreased NO(*) levels-similar to what is observed in G6PD-deficient endothelial cells. Aldosterone decreased G6PD expression by increasing expression of the cyclic AMP-response element modulator (CREM) to inhibit cyclic AMP-response element binding protein (CREB)-mediated G6PD transcription. In vivo, infusion of aldosterone decreased vascular G6PD expression and impaired vascular reactivity. These effects were abrogated by spironolactone or vascular gene transfer of G6pd. These findings demonstrate that aldosterone induces a G6PD-deficient phenotype to impair endothelial function; aldosterone antagonism or gene transfer of G6pd improves vascular reactivity by restoring G6PD activity.

show abstract

Section: Discussionmentioning

confidence: 79%

Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity

Leopold

Dam

Maron

et al. 2007

Nat Med

Self Cite

312

259

View full text Add to dashboard Cite

show abstract

“…Adequate availability of G-6-PD is needed to maintain both NO levels and preserve the proper redox milieu. It has been proposed that a G-6-PD-deficient phenotype could be present in critical vascular tissues in G-6-PD-deficient individuals and perhaps even in sickle cell disease patients with a normal G-6-PD genotype [116]. Relative G-6-PD deficiency might occur in the endothelium and play a role in the endothelium-related pathophysiology of disease.…”

Section: Erythrocyte Glucose-6-phosphate Dehydrogenase (G-6-pd) Deficmentioning

confidence: 99%

Genetic Etiologies for Phenotypic Diversity in Sickle Cell Anemia

Steinberg

2009

The Scientific World JOURNAL

167

122

View full text Add to dashboard Cite

The clinical course of patients with sickle cell anemia, a Mendelian trait, is characteristically highly variable. HbF concentration and the presence of a thalassemia are established modulators of the disease, but cannot account for all of its clinical heterogeneity. To find additional genetic modulators of disease, genotype-phenotype association studies, where single nucleotide polymorphisms (SNPs) in candidate genes are linked with a particular phenotype, have been informative. SNPs in several genes of the TGF-ß/MP superfamily, and some other genes linked to the endothelial function, and nitric oxide biology are associated with the subphenotypes of stroke, osteonecrosis, priapism, leg ulcers, pulmonary hypertension, and a more general measure of overall disease severity. Genome-wide association studies should help to confirm these observations and also to find hitherto unsuspected genetic modulators. Genetic association studies can have immediate prognostic value; they might also help to identify new pathophysiological pathways that could be susceptible to modulation.

show abstract

“…Oxidative stress is known to breach the endothelial barrier leading the inflammatory cells to filter into the perivascular space. Therefore, it is not surprising that G6PD mutations in humans are associated with endothelial dysfunction [ 164 ].…”

Section: Metabolic Implications Of G6pd Deficiency In Various Organs and Tissuesmentioning

confidence: 99%

The Controversial Role of Glucose‐6‐Phosphate Dehydrogenase Deficiency on Cardiovascular Disease: A Narrative Review

Dore

Parodi

Portoghese

2021

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Cardiovascular disorders (CVD) are highly prevalent and the leading cause of death worldwide. Atherosclerosis is responsible for most cases of CVD. The plaque formation and subsequent thrombosis in atherosclerosis constitute an ongoing process that is influenced by numerous risk factors such as hypertension, diabetes, dyslipidemia, obesity, smoking, inflammation, and sedentary lifestyle. Among the various risk and protective factors, the role of glucose-6-phosphate dehydrogenase (G6PD) deficiency, the most common inborn enzyme disorder across populations, is still debated. For decades, it has been considered a protective factor against the development of CVD. However, in the recent years, growing scientific evidence has suggested that this inherited condition may act as a CVD risk factor. The role of G6PD deficiency in the atherogenic process has been investigated using in vitro or ex vivo cellular models, animal models, and epidemiological studies in human cohorts of variable size and across different ethnic groups, with conflicting results. In this review, the impact of G6PD deficiency on CVD was critically reconsidered, taking into account the most recent acquisitions on molecular and biochemical mechanisms, namely, antioxidative mechanisms, glutathione recycling, and nitric oxide production, as well as their mutual interactions, which may be impaired by the enzyme defect in the context of the pentose phosphate pathway. Overall, current evidence supports the notion that G6PD downregulation may favor the onset and evolution of atheroma in subjects at risk of CVD. Given the relatively high frequency of this enzyme deficiency in several regions of the world, this finding might be of practical importance to tailor surveillance guidelines and facilitate risk stratification.

show abstract

The A376G(A+) variant of the glucose-6-phosphate dehydrogenase gene is associated with endothelial dysfunction in African Americans

Cited by 8 publications

References 0 publications

Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity

Aldosterone impairs vascular reactivity by decreasing glucose-6-phosphate dehydrogenase activity

Genetic Etiologies for Phenotypic Diversity in Sickle Cell Anemia

The Controversial Role of Glucose‐6‐Phosphate Dehydrogenase Deficiency on Cardiovascular Disease: A Narrative Review

Contact Info

Product

Resources

About