NAD(P)H oxidase p22phox gene C242T polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics

Castejón, Ana M.; Bracero, J; Hoffmann, I S; Alfieri, Anna B.; Cubeddu, LX

doi:10.1038/sj.jhh.1002057

Cited by 26 publications

(19 citation statements)

References 40 publications

(79 reference statements)

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“…Castejón et al (12) reported lower nitric oxide (NO) metabolites levels in individuals with the TT genotype, and they concluded that increased NADPH oxidase-dependent superoxide production could affect NO bioactivity. Kals et al (31) showed the relationship between high-grade oxidative stress and increased arterial stiffness.…”

Section: Discussionmentioning

confidence: 99%

Association between the C242T polymorphism in the p22phox gene with arterial stiffness in the Brazilian population

Alvim

Santos

Dias

et al. 2012

Physiological Genomics

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oxidase p22phox subunit is responsible for the production of reactive oxygen species in the vascular tissue. The C242T polymorphism in the p22phox gene has been associated with diverse coronary artery disease phenotypes, but the findings about the protective or harmful effects of the T allele are still controversial. Our main aim was to assess the effect of p22phox C242T genotypes on arterial stiffness, a predictor of late morbidity and mortality, in individuals from the general population. We randomly selected 1,178 individuals from the general population of Vitoria City, Brazil. Genotypes for the C242T polymorphism were detected by PCR-RFLP, and pulse wave velocity (PWV) values were measured with a noninvasive automatic device Complior. p22phox and TNF-␣ gene expression were quantified by real-time PCR in human arterial mammary smooth muscle cells. In both the entire and nonhypertensive groups: individuals carrying the TT genotype had higher PWV values and higher risk for increased arterial stiffness [odds ratio (OR) 1.93, 95% confidence interval (CI) 1.27-2.92 and OR 1.78, 95% CI 1.07-2.95, respectively] compared with individuals carrying CCϩCT genotypes, even after adjustment for covariates. No difference in the p22phox gene expression according C242T genotypes was observed. However, TNF-␣ gene expression was higher in cells from individual carrying the T allele, suggesting that this genetic marker is associated with functional phenotypes at the gene expression level. In conclusion, we suggest that p22phox C242T polymorphism is associated with arterial stiffness evaluated by PWV in the general population. This genetic association shed light on the understanding of the genetic modulation on vascular dysfunction mediated by NADPH oxidase. pulse wave velocity; NADPH oxidase; reactive oxygen species; coronary artery disease NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE (NADPH) oxidase is a source of reactive oxygen species (ROS), including superoxide and hydrogen peroxide in vascular smooth muscle and endothelial cells (2, 19 -21). The NADPH oxidase system is composed of multiple subunits of membrane (p22phox and gp91phox) and cytosolic (gp40 phox, gp47 phox, gp67 phox, and rac1) components that assemble on the cellular surface to generate ROS (13). Among these subunits the p22phox is highlighted as an essential membrane-associated factor that forms heterodimer with another membrane-integrated protein, gp91phox, or its homolog and plays a crucial role in the activation and stabilization of NADPH oxidase (4).The C242T polymorphism in the p22phox gene, which histidine is replaced by a tyrosine at position 72 and located in the putative heme-binding site of the p22phox subunit, has been associated with NADPH oxidase activity and, in addition, with increased risk and progression for coronary atherosclerosis and thrombotic cerebral infarction (9,18,43,48). Several epidemiological studies reported that increased arterial stiffness predicts mortality and morbidity, independently of other cardiovascular risk factors (6,8,...

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Section: Discussionmentioning

confidence: 99%

Association between the C242T polymorphism in the p22phox gene with arterial stiffness in the Brazilian population

Alvim

Santos

Dias

et al. 2012

Physiological Genomics

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“…Functionally, an impaired NAD(P)H oxidase activity has been linked to enhanced generation of cytotoxic NO derivates (e.g. peroxynitrite), abnormal pressor responses [11] , enhanced salt sensitivity [12] and a procoagulant state [13] as well as postinfarction inflammation and hypercholesterolemia [14] . From our experience of performing genotype analysis in a typical population of elderly stroke patients, we note that in older subjects weak associations are more likely to be masked by the high prevalence of conventional vascular risk factors than in a population of juvenile patients with a lower burden of risk factors.…”

Section: Discussionmentioning

confidence: 99%

The C242T Polymorphism of the NAD(P)H Oxidase p22phox Subunit Is Associated with an Enhanced Risk for Cerebrovascular Disease at a Young Age

Genius

Grau²,

Lichy³

2008

Cerebrovasc Dis

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Background and Purpose: Oxidative stress has been proposed as a major contributing factor for vascular disease, that acts independently from its participation in predisposing disorders such as diabetes and arterial hypertension. A functionally relevant C242T polymorphism of the CYBA gene encoding the NAD(P)H oxidase p22phox subunit, is supposed to lead to an abnormal reduction in the generation of reactive oxygen species in vascular smooth-muscle and endothelial cells. Methods: We investigated the p22phox C242T single-nucleotide polymorphism by polymerase chain reaction in consecutive patients with ischemic stroke or transient ischemic attack under the age of 50 (n = 161) and in population-based control subjects (n = 136). Results: Homozygosity for the T variant was associated with an enhanced risk for cerebral ischemia (odds ratio 3.85, confidence interval 1.39–10.64) after adjusting for classical risk factors. Risk for cerebral ischemia was not increased in heterozygous subjects. Conclusion: The p22phox C242T single-nucleotide polymorphism is associated with stroke risk. This finding supports the hypothesis that oxidative stress may contribute to stroke pathogenesis.

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“…One study also reports equal risk for cardiovascular risk factors, but increased salt sensitivity and decreased levels of nitric oxide metabolites in His72Tyr carriers (129).…”

Section: Subunits and Regulatory Proteinsmentioning

confidence: 99%

The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

Bedard¹,

Krause²

2007

Physiological Reviews

5,849

117

5,778

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For a long time, superoxide generation by an NADPH oxidase was considered as an oddity only found in professional phagocytes. Over the last years, six homologs of the cytochrome subunit of the phagocyte NADPH oxidase were found: NOX1, NOX3, NOX4, NOX5, DUOX1, and DUOX2. Together with the phagocyte NADPH oxidase itself (NOX2/gp91phox), the homologs are now referred to as the NOX family of NADPH oxidases. These enzymes share the capacity to transport electrons across the plasma membrane and to generate superoxide and other downstream reactive oxygen species (ROS). Activation mechanisms and tissue distribution of the different members of the family are markedly different. The physiological functions of NOX family enzymes include host defense, posttranlational processing of proteins, cellular signaling, regulation of gene expression, and cell differentiation. NOX enzymes also contribute to a wide range of pathological processes. NOX deficiency may lead to immunosuppresion, lack of otoconogenesis, or hypothyroidism. Increased NOX actvity also contributes to a large number or pathologies, in particular cardiovascular diseases and neurodegeneration. This review summarizes the current state of knowledge of the functions of NOX enzymes in physiology and pathology.

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NAD(P)H oxidase p22phox gene C242T polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics

Cited by 26 publications

References 40 publications

Association between the C242T polymorphism in the p22phox gene with arterial stiffness in the Brazilian population

Association between the C242T polymorphism in the p22phox gene with arterial stiffness in the Brazilian population

The C242T Polymorphism of the NAD(P)H Oxidase p22<sup>phox</sup> Subunit Is Associated with an Enhanced Risk for Cerebrovascular Disease at a Young Age

The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology

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