Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia

Weiss, Norbert; Keller, C.; Hoffmann, Ulrich; Loscalzo, Joseph

doi:10.1191/1358863x02vm428ra

Cited by 138 publications

(94 citation statements)

References 181 publications

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“…The most common genetic cause of mild HHcy is the expression of a MTHFR variant. In these patients there is an increased incidence of venous thrombosis and arterial atherothrombotic diseases, including myocardial infarction and stroke (25)(26)(27). To address our hypothesis, we have selected newly diagnosed patients from this latter group who are MTHFR++ carriers with higher levels of Hcy.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…It is well known that a key event associated with hyperhomocysteinemia is the induction of endothelial dysfunction which is implicated in the pathophysiology of different forms of cardiovascular diseases [1][2][3][4]13]. Moreover, the process of cell adhesion has been suggested to be an important step in the initiation and development of inflammatory processes associated with atherosclerosis [13].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the process of cell adhesion has been suggested to be an important step in the initiation and development of inflammatory processes associated with atherosclerosis [13].…”

Section: Introductionmentioning

confidence: 99%

Homocysteine‐induced endothelial cell adhesion is related to adenosine lowering and is not mediated by S‐adenosylhomocysteine

et al. 2007

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Hyperhomocysteinemia is a cardiovascular risk factor and may contribute to the pathogenesis of atherosclerosis by altering endothelial functions. The mechanism of homocysteine-induced cell adhesion has been here investigated using EA.hy 926 cells. Homocysteine induces a stereospecific, time-and dosedependent cell adhesion which is prevented by adenosine. The dramatic increase of S-adenosylhomocysteine induced by adenosine-2 0 ,3 0 -dialdehyde does not cause cell adhesion, indicating that no apparent relationship exists between this process and intracellular S-adenosylhomocysteine content. Homocysteine-induced cell adhesion is abolished by pre-treatment with adenosine-2 0 ,3 0 -dialdehyde, demonstrating that the adenosine depletion caused by reversal of S-adenosylhomocysteine hydrolase reaction is responsible for homocysteine-induced cell damage.

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“…The resulting endothelial dysfunction is contributory to decreased vasodilator capacity, activation of circulating leukocytes and platelets, activation of prothrombotic and inhibition of fibrinolytic mechanisms, and stimulation of vascular smooth muscle cell proliferation. All these effects participate in the initiation and progression of atherosclerotic lesions and thrombus formation (1). The purpose of this article is to review recent advances in understanding the mechanisms by which elevated levels of homocysteine induce vascular oxidant stress, and the impact of such stress on endothelial function in the clinical setting.…”

Section: Introductionmentioning

confidence: 99%

Influence of Hyperhomocysteinemia on the Cellular Redox State – Impact on Homocysteine-Induced Endothelial Dysfunction

Weiss

Heydrick²,

Postea³

et al. 2003

Clinical Chemistry and Laboratory Medicine

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Hyperhomocysteinemia is an independent risk factor for the development of atherosclerosis. An increasing body of evidence has implicated oxidative stress as being contributory to homocysteine's deleterious effects on the vasculature. Elevated levels of homocysteine may lead to increased generation of superoxide by a biochemical mechanism involving nitric oxide synthase, and, to a lesser extent, by an increase in the chemical oxidation of homocysteine and other aminothiols in the circulation. The resultant increase in superoxide levels is further amplified by homocysteinedependent alterations in the function of cellular antioxidant enzymes such as cellular glutathione peroxidase or extracellular superoxide dismutase. One direct clinical consequence of elevated vascular superoxide levels is the inactivation of the vasorelaxant messenger nitric oxide, leading to endothelial dysfunction. Scavenging of superoxide anion by either superoxide dismutase or 4,5-dihydroxybenzene 1,3-disulfonate (Tiron) reverses endothelial dysfunction in hyperhomocysteinemic animal models and in isolated aortic rings incubated with homocysteine. Similarly, homocysteine-induced endothelial dysfunction is also reversed by increasing the concentration of the endogenous antioxidant glutathione or overexpressing cellular glutathione peroxidase in animal models of mild hyperhomocysteinemia. Taken together, these findings strongly suggest that the adverse vascular effects of homocysteine are at least partly mediated by oxidative inactivation of nitric oxide.

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Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia

Cited by 138 publications

References 181 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

Homocysteine‐induced endothelial cell adhesion is related to adenosine lowering and is not mediated by S‐adenosylhomocysteine

Influence of Hyperhomocysteinemia on the Cellular Redox State – Impact on Homocysteine-Induced Endothelial Dysfunction

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