Homocysteine induces oxidative stress by uncoupling of no synthase activity through reduction of tetrahydrobiopterin

Topal, Gökçe; Brunet, Annie; Millanvoye, Elisabeth; Boucher, Jean‐Luc; Rendu, Francine; Devynck, Marie‐Aude; David‐Dufilho, Monique

doi:10.1016/j.freeradbiomed.2004.03.019

Cited by 145 publications

(113 citation statements)

References 45 publications

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“…Endothelial dysfunction has been linked to reduced BH4 availability and uncoupling of eNOS [15,36,37]. Various clinical studies have also demonstrated that administration of BH4 improves endothelial dysfunction in conditions characterized by reduced availability of NO and increased production of reactive oxygen species, such as hypercholesterolemia [38], coronary artery disease [24] and smoking [39].…”

Section: Discussionmentioning

confidence: 99%

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

Singh

Devaraj

Vásquez‐Vivar

et al. 2007

Journal of Molecular and Cellular Cardiology

119

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C-reactive protein (CRP), a cardiovascular risk marker, induces endothelial dysfunction. We have previously shown that CRP decreases endothelial nitric oxide synthase (eNOS) expression and bioactivity in human aortic endothelial cells (HAECs). In this study, we examined the mechanisms by which CRP decreases eNOS activity in HAECs. To this end, we explored different strategies such as availability of tetrahydrobiopterin (BH4) -a critical cofactor for eNOS, superoxide (O 2 -) production resulting in uncoupling of eNOS and phosphorylation/dephosphorylation of eNOS. CRP treatment significantly decreased levels of BH4 thereby promoting eNOS uncoupling. Pretreatment with sepiapterin, a BH4 precursor, prevented CRP-mediated effects on BH 4 levels, superoxide production as well as eNOS activity. The gene expression and enzymatic activity of GTPCH1, the first enzyme in the de novo biosynthesis of BH 4 , was significantly inhibited by CRP. Importantly, GTPCH1 is known to be regulated by cAMP mediated pathway. In the present study, CRP mediated inhibition of GTPCH1 activity was reversed by pretreatment with cAMP analogues. Furthermore, CRP-induced O 2 -production was reversed by pharmacologic inhibition and siRNAs to p47 phox and p22 phox. Additionally, CRP treatment significantly decreased the eNOS dimer:monomer ratio confirming CRP-mediated eNOS uncoupling. The pretreatment of cells with NO synthase inhibitor (N-nitro-L-arginine methyl ester [L-NAME]) also prevented CRP-mediated O 2 -production further strengthening CRP-mediated eNOS uncoupling. Additionally, CRP decreased eNOS phosphorylation at Ser1177 as well as increased phosphorylation at Thr495. CRP appears to mediate these effects through the Fcγ receptors, CD32 and CD64.To conclude, CRP uncouples eNOS resulting in increased superoxide production, decreased NO production, altered eNOS phosphorylation.

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Section: Discussionmentioning

confidence: 99%

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

Singh

Devaraj

Vásquez‐Vivar

et al. 2007

Journal of Molecular and Cellular Cardiology

119

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“…Homocysteine induces endothelial dysfunction through an inhibition of lysyl oxidase (LOX) and repression of LOX expression (Raposo et al, 2004). Topal et al (2004) reported that homocysteine induced oxidative stress, which causes vascular damage by inactivating endothelial NO synthase through a reduction of the cofactor tetrahydrobiopterin in human endothelial cells. Homocysteine also diminishes prostacyclin production through inhibition of cyclooxygenase activity (Quere et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Homocysteine accumulation causes a defect in purine biosynthesis: further characterization of Schizosaccharomyces pombe methionine auxotrophs

et al. 2006

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Methionine synthase (EC2.1.1.14) catalyses the final step in methionine synthesis, i.e. methylation of homocysteine. A search of the Schizosaccharomyces pombe genomic database revealed a gene designated SPAC9.09, encoding a protein with significant homology to methionine synthase. Disruption of SPAC9.09 caused methionine auxotrophy, and thus the gene was identified as a methionine synthase and designated met26. The met26 mutant was found to exhibit a remarkable growth defect in the absence of adenine even in medium supplemented with methionine. This phenotype was not observed in other methionine auxotrophs. In the budding yeast Saccharomyces cerevisiae, which has been reported to utilize homocysteine in cysteine synthesis, lack of a functional methionine synthase did not cause a requirement for adenine. The introduction of genes from Sac. cerevisiae constituting the cystathionine pathway (CYS4 and CYS3) into Sch. pombe Δmet26 cells restored growth in the absence of adenine. HPLC analysis showed that total homocysteine content in Δmet26 cells was higher than in other methionine auxotrophs and that introduction of the Sac. cerevisiae cystathionine pathway decreased total homocysteine levels. These data demonstrate that accumulation of homocysteine causes a defect in purine biosynthesis in the met26 mutant.

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“…In the last period, evidence concerning homocysteine involvement in thrombosis and cardiovascular diseases has been accumulated [1][2][3][4][5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Hyperhomocysteinemia’s effect on antioxidant capacity in rats

et al. 2010

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AbstractHyperhomocysteinemia represents elevated homocysteine (Hcys) concentrations in blood above the normal range. In humans, the normal range of homocysteine is 5.0–15.9 mM/ml. High levels of homocysteine disturb the normal epithelial functions and correlate with cardiovascular diseases even at slightly increased concentrations. In homocysteine metabolism, vitamins play an important role. The mechanism through which homocysteine triggers these effects is not yet elucidated, but the involvement of reactive species may be the answer. It is not known whether the intra- or extracellular antioxidant system is more affected by elevated homocysteine levels. We studied the effects of hyperhomocysteinemia on the intra- and extracellular antioxidant defense systems in two different types of diet in rats. Type I was food with low folic acid and vitamin B12 content and type II was food with normal amounts of these two vitamins. Hyperhomocysteinemia was experimentally induced by oral administration of methionine 2 mg/kg body weight, single daily dose, for a 15-day period. Plasma concentrations of homocysteine were measured using an HPLC method. In the response of the intracellular antioxidant defense system against hyperhomocysteinemia, we determined the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) in red blood cells, using RANDOX kits for manual use. For the extracellular response we determined the plasma total antioxidant status (TAS) also using a RANDOX kit for manual use. Our data show that methionine load induces hyperhomocysteinemia despite normal vitamin supply in rats. SOD activity rose with simultaneous decrease in GPx activity independently of diet; this might suggest that the intracellular defense system was disturbed by the rise in homocysteine level. TAS decrease suggests that the extracellular antioxidant defense was also affected. We assume that hyperhomocysteinemia is directly linked to reactive species generation and the intracellular space seems to be more affected than the extracellular one.

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Homocysteine induces oxidative stress by uncoupling of no synthase activity through reduction of tetrahydrobiopterin

Cited by 145 publications

References 45 publications

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

C-reactive protein decreases endothelial nitric oxide synthase activity via uncoupling

Homocysteine accumulation causes a defect in purine biosynthesis: further characterization of Schizosaccharomyces pombe methionine auxotrophs

Hyperhomocysteinemia’s effect on antioxidant capacity in rats

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