Oxidative Stress and Platelet Activation in Homozygous Homocystinuria

Davı̀, Giovanni; Minno, Giovanni Di; Coppola, Antonio; Andria, Generoso; Cerbone, A.M.; Madonna, Pasquale; Tufano, Antonella; Falco, Angela; Marchesani, Paola; Ciabattoni, Giovanni; Patrono, Carlo

doi:10.1161/hc3501.095287

Cited by 115 publications

(67 citation statements)

References 29 publications

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“…In HHcy patients, increased platelet activation has been associated with elevated production of tromboxane A 2 (28)(29)(30). In line with these findings, in MTHFR++ carriers, we found that urine thromboxane metabolites were significantly higher than in healthy individuals.…”

Section: Discussionsupporting

confidence: 88%

Hydrogen sulphide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia

Bianca

Mitidieri

Minno

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Homocysteine is metabolized to methionine by the action of 5,10methylenetetrahydrofolate reductase (MTHFR). Alternatively, by thetransulfuration pathway, homocysteine is transformed to hydrogen sulphide (H2S),through multiple steps involving cystathionine beta-synthase and cystathioninegamma-lyase. Here we have evaluated the involvement of H2S in the thromboticevents associated with hyperhomocysteinemia. To this purpose we have usedplatelets harvested from healthy volunteers or patients newly diagnosed withhyperhomocysteinemia with a C677T polymorphism of the MTHFR gene (MTHFR++). NaHS(0.1-100 microM) or l-cysteine (0.1-100 microM) significantly increased plateletaggregation harvested from healthy volunteers induced by thrombin receptoractivator peptide-6 amide (2 microM) in a concentration-dependent manner. Thisincrease was significantly potentiated in platelets harvested from MTHFR++carriers, and it was reversed by the inhibition of either cystathioninebeta-synthase or cystathionine gamma-lyase. Similarly, in MTHFR++ carriers, thecontent of H2S was significantly higher in either platelets or plasma comparedwith healthy volunteers. Interestingly, thromboxane A2 production was markedlyincreased in response to both NaHS or l-cysteine in platelets of healthyvolunteers. The inhibition of phospholipase A2, cyclooxygenase, or blockade ofthe thromboxane receptor markedly reduced the effects of H2S. Finally,phosphorylated-phospholipase A2 expression was significantly higher in MTHFR++carriers compared with healthy volunteers. In conclusion, the H2S pathway isinvolved in the prothrombotic events occurring in hyperhomocysteinemic patients

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Section: Discussionsupporting

confidence: 88%

Hydrogen sulphide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia

Bianca

Mitidieri

Minno

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The results of this intervention study are consistent with COX-1 being the main COX isoform involved in TXA 2 biosynthesis in this setting and make it unlikely that the reduction in 11-dehydro-TXB 2 excretion associated with successful H pylori eradication is a reflection of reduced COX-2 expression in the gastric mucosa. 16 The findings in H pylori-positive patients extend similar observations made in other clinical settings such as hypercholesterolemia, 42 diabetes mellitus, 43 cigarette smoking, 48,49 homozygous homocystinuria, 50 visceral obesity, 44 and renovascular hypertension. 51 Thus, regardless of the mechanism(s) responsible for enhanced lipid peroxidation, there is quite convincing evidence from studies in such diverse conditions that enhanced generation of bioactive isoeicosanoids may transduce the oxidant signal associated with a variety of cardiovascular risk factors into a functional platelet response, possibly contributing to enhanced thrombotic risk.…”

Section: Discussionsupporting

confidence: 83%

44 Helicobacter pylori infection causes persistent platelet activation in vivo through enhanced lipid peroxidation

2005

Nutrition, Metabolism and Cardiovascular Diseases

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Objective-We aimed at investigating the relationship between Helicobacter pylori infection and in vivo lipid peroxidation and platelet activation, as reflected by urinary 8-iso-prostaglandin (PG)F 2␣ and 11-dehydro-thromboxane (TX)B 2 , respectively, in otherwise healthy dyspeptic subjects. Methods and Results-We measured urinary 8-iso-PGF 2␣ and 11-dehydro-TXB 2 excretion in 40 dyspeptic subjects with a positive 13 C-urea breath test and 38 dyspeptic individuals with a negative test. Moreover, we investigated the effects of H pylori eradication on prostanoid metabolite excretion in 23 H pylori-positive subjects. We also measured prostanoid metabolite excretion before and after selective cyclooxygenase-2 inhibition with rofecoxib in 4 H pylori-positive subjects. Urinary 8-iso-PGF 2␣ and 11-dehydro-TXB 2 excretion was significantly higher in the H pylori-positive individuals than in controls. A significant direct correlation was found between the degree of positivity to the 13 C-urea breath test and urinary 8-iso-PGF 2␣ excretion. The latter was linearly correlated with urinary 11-dehydro-TXB 2 . Successful eradication of H pylori infection led to a significant reduction in both 8-iso-PGF 2␣ and 11-dehydro-TXB 2 . Furthermore, their levels were unaffected after treatment with rofecoxib. Conclusions-Our study provides evidence of enhanced in vivo lipid peroxidation and platelet activation in association with H pylori infection and suggests a novel mechanism by which an infectious agent could contribute to atherothrombosis.

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“…CS-induced platelet activation is mainly attributed to its oxidant content and its ability to generate ROS, specifically superoxide anion 32) ; therefore, vitamin C by neutralizing systemic ROS may inhibit CS-induced platelet activation and can contribute to its anti-atherosclerotic property. Consistent with this hypothesis, our results showed that vitamin C, in a dose-dependent manner, prevented CSEinduced platelet activation and thereby provided protection against the development of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

Vitamin C Prevents Cigarette Smoke Induced Atherosclerosis in Guinea Pig Model

Ray

Maity

Banerjee³

et al. 2010

JAT

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Aim: Cigarette smoking is a major risk for developing atherosclerosis; however, the underlying mechanism is poorly understood. This paucity of knowledge is largely attributed to the lack of an animal model; therefore, our efforts were targeted towards establishing cigarette smoke (CS)-induced atherosclerosis in guinea pig. To understand the mechanism, we investigated apoptosis, an event implicated in atherosclerosis, in the aorta of CS-exposed animals. Since a major deleterious effect of CS is oxidative stress, we also examined the effect of vitamin C, an antioxidant, on CS-induced atherosclerosis. Methods and Results: Guinea pigs on a diet with or without vitamin C supplement were exposed to CS for different time periods. Aortal sections from these animals were examined for atherosclerotic changes by staining with H&E and Oil red O. Atherogenic changes were observed in sections obtained from CS-exposed guinea pigs only. TUNEL assay showed the occurrence of apoptosis in CS-exposed guinea pig aorta. Our results revealed that CS-induced apoptosis could contribute to the progression but not to the initiation of the disease. Immunohistochemical analysis documents that CS-induced apoptosis in aortal sections is mediated at least in part by an increased Bax/Bcl2 ratio. In contrast, CS-exposed guinea pigs fed with vitamin C-supplemented diet exhibit little or no atherogenic changes. This anti-atherosclerotic activity of vitamin C can be attributed partly to its ability to inhibit CS-induced apoptosis and platelet activation. Conclusion: Exposure of guinea pigs to cigarette smoke causes the development of atherosclerosis, which can be prevented by vitamin C supplement.

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Oxidative Stress and Platelet Activation in Homozygous Homocystinuria

Cited by 115 publications

References 29 publications

Hydrogen sulphide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia

Hydrogen sulphide pathway contributes to the enhanced human platelet aggregation in hyperhomocysteinemia

44 Helicobacter pylori infection causes persistent platelet activation in vivo through enhanced lipid peroxidation

Vitamin C Prevents Cigarette Smoke Induced Atherosclerosis in Guinea Pig Model

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