Channeling the homocysteine chapel

Sibinga, Nicholas E.S.

doi:10.1182/blood-2011-06-361360

Cited by 3 publications

(1 citation statement)

References 13 publications

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“…Although a great number of studies shows that elevated homocysteine levels clearly contribute to the development of thrombosis and the ensuing complications (23-25), there are data suggesting that elevated homocysteine levels are merely a consequence and not the cause of vascular disease (26). The proposed pathophysiological mechanisms by which hyperhomocysteinemia disrupts vascular physiology and contributes to the development of thrombosis include endothelial dysfunction as result of oxidation and tyrosine nitration of small and intermediate conductance Ca 2+ -activated potassium channels resulting in impaired endothelium-derived hyperpolarizing factor-mediated relaxation of resistance arterioles (27-29), oxidative modification of low density lipoproteins (LDL) particles (30), increase in lipid uptake and retention by blood vessel walls, increased adhesion of monocytes to the blood vessel wall, stimulation of smooth muscle proliferation (31), activation of inflammatory pathways (32), thrombocytic dysfunction (33), and activation of procoagulant factors of the hemostatic mechanism (27). …”

Section: Discussionmentioning

confidence: 99%

Clinical significance of determining plasma homocysteine: case-control study on arterial and venous thrombotic patients

Vučković¹,

Čabarkapa²,

Ilić³

et al. 2013

Croat Med J

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AimTo determine the differences in plasma homocysteine levels between three MTHFR 677 genotype subgroups in patients with thrombosis and in controls, as well as between patients with thrombosis and controls with the same MTHFR 677 genotype.MethodsThis case-control study was conducted in Clinical Center of Vojvodina, Novi Sad, from June to December 2011. We included 65 patients with either arterial or venous thrombosis (mean age, 40.97 ± 11.38 years) and 65 controls with no history or clinical evidence of any thrombotic event (mean age, 41.23 ± 11.12 years). Patients and controls were age- and sex-matched.ResultsIn comparison with controls, thrombotic patients had significantly higher homocysteine levels (12.81 ± 4.94 µmol/L vs 9.82 ± 3.68 µmol/L; P < 0.001) and significantly higher incidence of hyperhomocysteinemia (55% vs 22%; P < 0.001; odds ratio [OR] = 4.521). There were no significant differences in homocysteine levels between homozygous carriers, heterozygous carriers, and non-carriers of the MTHFR 677 mutation in either thrombotic patients (12.97 ± 5.40 µmol/L vs 12.55 ± 5.71 µmol/L vs 13.27 ± 1.71 µmol/L; P = 0.100) or controls (10.07 ± 2.50 µmol/L vs 10.25 ± 4.84 µmol/L vs 9.20 ± 2.44 µmol/L; P = 0.651). However, in comparison with controls, homozygous carriers in thrombotic patient group did not have significantly higher levels of homocysteine (12.97 ± 5.40 µmol/L vs 10.07 ± 2.50 µmol/L; P = 0.072), but heterozygous carriers (12.55 ± 5.71 µmol/L vs 10.25 ± 4.84 µmol/L; P = 0.020) and non-carriers (13.27 ± 1.71 µmol/L vs 9.20 ± 2.44 µmol/L; P < 0.001) did. There was no significant difference in homocysteine levels between patients with arterial and venous thrombosis (12.76 ± 3.60 µmol/L vs 12.86 ± 5.51 µmol/L; P = 0.990) and between patients with one thrombotic event and those with recurrent thrombotic events (12.14 ± 3.20 µmol/L vs 15.25 ± 8.51 µmol/L; P = 0.254).ConclusionPlasma homocysteine levels have a greater clinical significance in the prevention of thrombosis and managing its complications than MTHFR 677 genotyping.

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Section: Discussionmentioning

confidence: 99%

Clinical significance of determining plasma homocysteine: case-control study on arterial and venous thrombotic patients

Vučković¹,

Čabarkapa²,

Ilić³

et al. 2013

Croat Med J

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Contribution of endogenously produced reactive oxygen species to the activation of podocyte NLRP3 inflammasomes in hyperhomocysteinemia

Abais

Xia

et al. 2014

Free Radical Biology and Medicine

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Hyperhomocysteinemia (hHcys) is an important pathogenic factor contributing to the progression of end-stage renal disease. Recent studies have demonstrated the implication of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated NLRP3 inflammasome activation in the development of podocyte injury and glomerular sclerosis during hHcys. However, it remains unknown which reactive oxygen species (ROS) are responsible for this activation of NLRP3 inflammasomes and how such action of ROS is controlled. The present study tested the contribution of common endogenous ROS including superoxide (O2•−), hydrogen peroxide (H2O2), and hydroxyl radical (•OH) to the activation of NLRP3 inflammasomes in mouse podocytes and glomeruli. In vitro, confocal microscopy and size exclusion chromatography demonstrated that dismutation of O2•− by 4-Hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL) and decomposition of H2O2 by catalase prevented Hcys-induced aggregation of NLRP3 inflammasome proteins and inhibited Hcys-induced caspase-1 activation and IL-1β production in mouse podocytes. However, •OH scavenger tetramethylthiourea (TMTU) had no significant effect on either Hcys-induced NLRP3 inflammasome formation or activation. In vivo, scavenging of O2•− by TEMPOL and removal of H2O2 by catalase substantially inhibited NLRP3 inflammasome formation and activation in glomeruli of hHcys mice as shown by reduced colocalization of NLRP3 with ASC or caspase-1 and inhibition of caspase-1 activation and IL-1β production. Furthermore, TEMPOL and catalase significantly attenuated hHcys-induced glomerular injury. In conclusion, endogenously produced O2•− and H2O2 primarily contribute to NLRP3 inflammasome formation and activation in mouse glomeruli resulting in glomerular injury or consequent sclerosis during hHcys.

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Inflammation, oxidative stress, and cardiovascular disease risk factors in adults with cystic fibrosis

Reverri¹,

Morrissey²,

Cross³

et al. 2014

Free Radical Biology and Medicine

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Channeling the homocysteine chapel

Cited by 3 publications

References 13 publications

Clinical significance of determining plasma homocysteine: case-control study on arterial and venous thrombotic patients

Clinical significance of determining plasma homocysteine: case-control study on arterial and venous thrombotic patients

Contribution of endogenously produced reactive oxygen species to the activation of podocyte NLRP3 inflammasomes in hyperhomocysteinemia

Inflammation, oxidative stress, and cardiovascular disease risk factors in adults with cystic fibrosis

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