158 research outputs found
Oxidative stress and vascular remodelling
Oxidative stress plays an important role in the pathophysiology of vascular diseases. Reactive
oxygen species, especially superoxide anion and hydrogen peroxide, are important signalling
molecules in cardiovascular cells. Enhanced superoxide production increases nitric oxide
inactivation and leads to an accumulation of peroxynitrites and hydrogen peroxide. Reactive
oxygen species participate in growth, apoptosis and migration of vascular smooth muscle cells,
in the modulation of endothelial function, including endothelium-dependent relaxation and
expression of proinflammatory phenotype, and in the modification of the extracellular matrix.
All these events play important roles in vascular diseases such as hypertension, suggesting that
the sources of reactive oxygen species and the signalling pathways that theymodifymay represent
important therapeutic targets. Potential sources of vascular superoxide production include
NADPH-dependent oxidases, xanthine oxidases, lipoxygenases, mitochondrial oxidases and
nitricoxide synthases. Studies performedduring the last decadehave shownthatNADPHoxidase
is the most important source of superoxide anion in phagocytic and vascular cells. Evidence from
experimental animal and human studies suggests a significant role ofNADPHoxidase activation
in the vascular remodelling and endothelial dysfunction found in cardiovascular diseases
RelaciĂłn entre las fases precoces de la enfermedad renal y el sĂndrome metabĂłlico
Advanced kidney disease is a major health problem
due to its association with high cardiovascular morbidity and mortality. Early
recognition of advanced kidney disease is the mainstay to avoid its progression.
Since metabolic syndrome and insulin resistance are risk factors for both
cardiovascular and advanced kidney disease, we investigated the relationship of
early kidney disease (EKD) with metabolic syndrome and insulin resistance, and
their association with surrogate markers of arteriosclerosis. METHODS: We studied
1498 subjects. Insulin resistance was defined as HOMA >/=3.7 mmol (muU)/L(2) and
EKD as stages 1 and 2 of the NKF-KDOQI. Carotid intima-media thickness was used
as a surrogate marker of arteriosclerosis. RESULTS: The presence of one trait of
metabolic syndrome was associated with an odds ratio (OR) for EKD of 2.3 (95%
confidence interval [CI], 1.18-4.48) that increased to 6.72 (95% CI, 3.56-13.69)
in subjects with the syndrome. All the traits of the syndrome except low level of
high-density lipoproteins showed an increased OR for EKD. Increasing HOMA was
also directly correlated with higher OR for EKD, being as high as 3.89 (95% CI,
1.99-7.59) for subjects in the fourth quartile. Subjects with the syndrome plus
EKD showed an increased intima-media thickness compared with those without kidney
disease. CONCLUSIONS: Insulin resistance and all metabolic syndrome traits except
low level of high-density lipoproteins were significantly associated with an
increased OR for EKD. Both metabolic syndrome and EKD were independently and
additively related to the presence of surrogate markers of arteriosclerosis
The inhibitory effect of leptin on angiotensin II-induced vasoconstriction in vascular smooth muscle cells is mediated via a nitric oxide-dependent mechanism
Leptin inhibits the contractile response induced by angiotensin (Ang) II in vascular smooth muscle cells (VSMCs) of the aorta. We studied in vitro and ex vivo the role of nitric oxide (NO) in the effect of leptin on the Ang II-induced vasoconstriction of the aorta of 10-wk-old Wistar rats. NO and nitric oxide synthase (NOS) activity were assessed by the Griess and (3)H-arginine/citrulline conversion assays, respectively. Stimulation of inducible NOS (iNOS) as well as Janus kinases/signal transducers and activators of transcription (JAK/STAT) and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways were determined by Western blot. The contractile responses to Ang II were evaluated in endothelium-denuded aortic rings using the organ bath system. Changes in intracellular Ca(2+) were measured in VSMCs using fura-2 fluorescence. Leptin significantly (P < or = 0.01) stimulated NO release and NOS activity in VSMCs. Leptin's effect on NO was abolished by the NOS inhibitor, N(G)-monomethyl l-arginine, or the iNOS selective inhibitor L-N(6)-(1-iminoethyl)-lysine. Accordingly, leptin increased iNOS protein expression, with a comparable time course with that of NO production and NOS activity. Leptin also significantly increased STAT3 (P < or = 0.01) and Akt (P < or = 0.001) phosphorylation. Moreover, either the JAK2 inhibitor, AG490, or the PI3K inhibitor, wortmannin, significantly (P < or = 0.05) abrogated the leptin-induced increase in iNOS protein. Finally, both N(G)-monomethyl L-arginine and L-N(6)-(1-iminoethyl)-lysine inhibitors completely blunted (P < or = 0.001) the leptin-mediated inhibition of the Ang II-induced VSMC activation and vasoconstriction. These findings suggest that the endothelium-independent depressor action of leptin is mediated by an increase of NO bioavailability in VSMCs. This process requires the up-regulation of iNOS through mechanisms involving JAK2/STAT3 and PI3K/Akt pathways
NADPH OxidaseâDependent Superoxide Production Is Associated With Carotid Intima-Media Thickness in Subjects Free of Clinical Atherosclerotic Disease
ObjectiveâOxidative stress plays a critical role in the pathogenesis of atherosclerosis. The NADPH oxidase constitutes the
main source of superoxide in phagocytic and vascular cells. This study aimed to investigate the levels of NADPH
oxidaseâmediated superoxide production in phagocytic cells and the association between phagocytic superoxide
production and carotid intima-media thickness (IMT), a surrogate marker of asymptomatic atherosclerosis.
Methods and ResultsâNADPH oxidaseâmediated superoxide production was determined by a chemiluminescence assay
using lucigenin and associated with IMT for 184 asymptomatic subjects free of overt clinical atherosclerotic disease.
Compared with individuals in the lowest tertile of superoxide production, those in the upper tertile ( 20 counts/sec)
showed significantly higher IMT (P 0.05). In correlation analysis, a positive relationship was found between
superoxide production and carotid IMT. Superoxide production also correlated positively (P 0.05) with body mass
index (BMI). In multivariate analysis, the association of superoxide production with carotid IMT remained significant
after adjustment for age, sex, systolic blood pressure, BMI, triglycerides, glucose, and smoking.
ConclusionsâIn a population sample of adults without clinically overt atherosclerotic disease, increased NADPH oxidase
activity was associated with enhanced carotid IMT, suggesting a relationship between phagocytic NADPH oxidaseâ
mediated oxidative stress and the development of atherosclerosis
Increased phagocytic nicotinamide adenine dinucleotide phosphate oxidaseâdependent superoxide production in patients with early chronic kidney disease
Background. Oxidative stress has been implicated in the
pathogenesis of atherosclerosis that develops in patients with
advanced chronic kidney disease (CKD). This study was
designed to investigate whether a relationship exists between
phagocytic nicotinamide adenine dinucleotide phosphate
(NADPH) oxidaseâdependent superoxide anion (âąO2
â) production
and subclinical atherosclerosis in patients with early
CKD.
Methods. Superoxide production was assayed by chemiluminescence
under baseline and stimulated conditions on mononuclear
cells obtained from asymptomatic patients with stage 1
to 2 CKD (N = 22) and healthy controls (N = 21). Ultrasonographic
determination of carotid intima-media thickness (IMT)
was used to assess the presence of atherosclerosis.
Results. Although there were no differences in baseline âąO2
â
production between controls and patients, the âąO2
â production
in phorbol myristate acetateâstimulated mononuclear cells was
increased (P < 0.05) in patients compared with controls. The
phorbol myristate acetateâinduced âąO2
â production was completely
abolished by apocynin, a specific inhibitor of NADPH
oxidase. A direct correlation (r = 0.441, P < 0.05) was found
between plasma insulin levels and NADPH oxidaseâmediated
âąO2
â production in patients. Carotid IMT was higher (P <
0.005) in patients than in controls. CarotidIMTvalues above the
upper normal limit in controls were found in 70% and 40% of
patients with increased or normal NADPH oxidaseâmediated
âąO2
â production, respectively.
Conclusion. Generation of âąO2
â that is mainly dependent on
NADPH oxidase is abnormally enhanced in patients with early
CKD. It is suggested that this alteration could be related to the
development of subclinical atherosclerosis in these patients
Polymorphisms and promoter overactivity of the p22(phox) gene in vascular smooth muscle cells from spontaneously hypertensive rats
In a previous study, we found that the p22(phox) subunit of the NADH/NADPH oxidase is overexpressed in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHRs) with enhanced vascular production of superoxide anion ((.)O(2)(-)). Thus, we have investigated whether changes in the sequence or activity of the promoter region of p22(phox) gene are present in SHRs. To carry out this analysis, first of all, we characterized the rat gene structure and promoter region for the p22(phox) subunit. The p22(phox) gene spans approximately 10 kb and contains 6 exons and 5 introns. Primer extension analysis indicated the transcriptional start site 100 bp upstream from the translational start site. The immediate promoter region of the p22(phox) gene does not contain a TATA box, but there are a CCAC box and putative recognition sites for nuclear factors, such as SP1, gamma-interferon, and nuclear factor-kappaB. Using reporter-gene transfection analysis, we found that this promoter was functional in VSMCs. Furthermore, we observed that p22(phox) promoter activity was significantly higher in VSMCs from SHRs than from normotensive Wistar-Kyoto rats. In addition, we found that there were 5 polymorphisms in the sequence of p22(phox) promoter between Wistar-Kyoto rats and SHRs and that they were functional. The results obtained in this study provide a tool to explore the mechanisms that regulate the expression of p22(phox) gene in rat VSMCs. Furthermore, our findings show that changes in the sequence of p22(phox) gene promoter and in the degree of activation of VSMCs are responsible for upregulated expression of p22(phox) in SHRs
Dietary total antioxidant capacity is associated with leukocyte telomere length in a children and adolescent population
Background & Aims: Oxidative stress and inflammation seem to be potential underlying mechanisms for telomere attrition. A lack of specific antioxidants is believed to increase free radical damage and a greater risk for telomere shortening. Our aim was to evaluate the relationship between diet and leukocyte telomere length in a cross-sectional study of children and adolescents. We hypothesized that dietary total antioxidant capacity would be positively associated with telomere length.
Methods: Telomere length was measured by quantitative real-time polymerase chain reaction in 287 participants (55% males, 6â18 years), who were randomly selected from the GENOI study.
Results: A positive correlation between dietary total antioxidant capacity and telomere length (r=0.157, p=0.007) was found after adjustment for age and energy intake. However, higher white bread consumption was associated with shorter telomeres (ÎČ=-0.204, p=0.002) in fully-adjusted models. Interestingly, those individuals who had simultaneously higher dietary total antioxidant capacity and lower white bread consumption significantly presented the longest telomeres. Moreover, the multivariable-adjusted odds ratio for very short telomeres was 0.30 for dietary total antioxidant capacity (p=0.023) and 1.37 for white bread (p=0.025).
Conclusion: It was concluded that longer telomeres were associated with higher dietary total antioxidant capacity and lower white bread consumption in S2panish children and adolescents. These findings might open a new line of investigation about the potential role of an antioxidant diet in maintaining telomere length
Functional Effect of the p22phox -930A/G Polymorphism on p22phox Expression and NADPH Oxidase Activity in Hypertension
Oxidative stress induced by superoxide is implicated in hypertension. NADPH oxidase is the main source of
superoxide in phagocytic and vascular cells, and the p22phox subunit is involved in NADPH oxidase activation. Recently
we reported an association of 930A/G polymorphism in the human p22phox gene promoter with hypertension. This study
was designed to investigate the functional role of this polymorphism in hypertension. We thus investigated the
relationships between the 930A/G polymorphism and p22phox expression and NADPH oxidaseâmediated superoxide
production in phagocytic cells from 70 patients with essential hypertension and 70 normotensive controls. Genotyping
of the polymorphism was performed by restriction fragment length polymorphism. NADPH oxidase activity was
determined by chemiluminescence assays, and p22phox mRNA and protein expression was measured by Northern and
Western blotting, respectively. Compared with hypertensive subjects with the AA/AG genotype, hypertensive subjects
with the GG genotype exhibited increased (P 0.05) phagocytic p22phox mRNA (1.26 0.06 arbitrary unit [AU] versus
0.99 0.03 AU) and protein levels (0.58 0.05 AU versus 0.34 0.04 AU) and enhanced NADPH oxidase activity
(1998 181 counts/s versus 1322 112 counts/s). No differences in these parameters were observed among genotypes
in normotensive cells. Transfection experiments on vascular smooth muscle cells showed that the A-to-G substitution
of this polymorphism produced an increased reporter gene expression in hypertensive cells. Nitric oxide production, as
assessed by measurement of serum nitric oxide metabolites, was lower in GG hypertensive subjects than in AA/AG
hypertensive subjects. In conclusion, these results suggest that hypertensive subjects carrying the GG genotype of the
p22phox 930A/G polymorphism are highly exposed to NADPH oxidase-mediated oxidative stress
Association of increased phagocytic NADPH oxidasedependent superoxide production with diminished nitric oxide generation in essential hypertension
Objective: Oxidative stress has been implicated in the pathogenesis of hypertension and its complications through alterations in nitric oxide (NO) metabolism. This study was designed to investigate whether a relationship exists between phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent superoxide anion (âąO2-) production and NO generation in patients with essential hypertension.
Methods: Superoxide production was assayed by chemiluminescence under baseline and stimulated conditions on mononuclear cells obtained from hypertensives (n = 51) and normotensives (n = 43). NO production was evaluated by determining serum NO metabolites, nitrate plus nitrite (NOx).
Results: Although there were no differences in baseline âąO2- production between normotensives and hypertensives, the âąO2- production in phorbol myristate acetate (PMA)-stimulated mononuclear cells was increased (P < 0.05) in hypertensives compared with normotensives. The PMA-induced âąO2- production was completely abolished by apocynin, a specific inhibitor of NADPH oxidase. Moreover, stimulation of âąO2- production by angiotensin II and endothelin-1 was higher (P < 0.05) in cells from hypertensives than in cells from normotensives. In addition, diminished (P < 0.001) serum NOx was detected in hypertensives compared with normotensives. Interestingly, an inverse correlation (r = 0.493, P < 0.01) was found between âąO2- production and NOx in hypertensives.
Conclusions: Generation of âąO2- mainly dependent on NADPH oxidase is abnormally enhanced in stimulated mononuclear cells from hypertensives. It is suggested that this alteration could be involved in the diminished NO production observed in these patients
Torasemide inhibits angiotensin II-induced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats
Torasemide is a loop diuretic that is effective at low once-daily doses in the treatment of arterial hypertension. Because its antihypertensive mechanism of action may not be based entirely on the elimination of salt and water from the body, a vasodilator effect of this drug can be considered. In the present study, the ability of different concentrations of torasemide to modify angiotensin II (Ang II)-induced vascular responses was examined, with the use of an organ bath system, in endothelium-denuded aortic rings from spontaneously hypertensive rats. Ang II-induced increases of intracellular free calcium concentration ([Ca(2+)](i)) were also examined by image analysis in cultured vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats. A dose-response curve to Ang II was plotted for cumulative concentrations (from 10(-9) to 10(-6) mol/L) in endothelium-denuded aortic rings (pD(2)=7.5+/-0.3). Isometric contraction induced by a submaximal concentration of Ang II (10(-7) mol/L) was reduced in a dose-dependent way by torasemide (IC(50)=0.5+/-0.04 micromol/L). Incubation of VSMCs with different concentrations of Ang II (from 10(-10) to 10(-6) mol/L) resulted in a dose-dependent rise of [Ca(2+)](i) (pD(2)=7.5+/-0.3). The stimulatory effect of [Ca(2+)](i) induced by a submaximal concentration of Ang II (10(-7) mol/L) was blocked by torasemide (IC(50)=0.5+/-0.3 nmol/L). Our findings suggest that torasemide blocks the vasoconstrictor action of Ang II in vitro. This action can be related to the ability of torasemide to block the increase of [Ca(2+)](i) induced by Ang II in VSMCs. It is proposed that these actions might be involved in the antihypertensive effect of torasemide observed in vivo
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