Homocysteinemia and Endothelial Damage after Methionine Load

Hladovec, J; Sommerová, Zuzana; Písařiacute, Alexandra; ková,

doi:10.1016/s0049-3848(97)00266-1

Cited by 24 publications

(12 citation statements)

References 4 publications

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“…However, very few TDAG51/TUNEL-positive endothelial cells were observed in early or mature atherosclerotic lesions from apoE Ϫ/Ϫ mice having diet-induced hyperhomocysteinemia. Because endothelial cells are increased in the circulation of patients with vascular disease following methionine load (46), it is possible that the majority of TDAG51/TUNELpositive endothelial cells may have lost their adhesive properties and were shed into the circulation. This would be consistent with our finding that TDAG51 overexpression causes a loss in cell adhesion prior to PCD.…”

Section: Discussionmentioning

confidence: 99%

TDAG51 Is Induced by Homocysteine, Promotes Detachment-mediated Programmed Cell Death, and Contributes to the Development of Atherosclerosis in Hyperhomocysteinemia

Hossain

Thienen

Werstuck

et al. 2003

Journal of Biological Chemistry

210

194

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Hyperhomocysteinemia is an independent risk factor for cardiovascular disease and accelerates atherosclerosis in apoE ؊/؊ mice. Despite the observations that homocysteine causes endoplasmic reticulum (ER) stress and programmed cell death (PCD) in cultured human vascular endothelial cells, the cellular factors responsible for this effect and their relevance to atherogenesis have not been completely elucidated. We report here that homocysteine induces the expression of T-cell death-associated gene 51 (TDAG51), a member of the pleckstrin homology-related domain family, in cultured human vascular endothelial cells. This effect was observed for other ER stress-inducing agents, including dithiothreitol and tunicamycin. TDAG51 expression was attenuated in homozygous A/A mutant eukaryotic translation initiation factor 2␣ mouse embryonic fibroblasts treated with homocysteine or tunicamycin, suggesting that ER stress-induced phosphorylation of eukaryotic translation initiation factor 2␣ is required for TDAG51 transcriptional activation. Transient overexpression of TDAG51 elicited significant changes in cell morphology, decreased cell adhesion, and promoted detachmentmediated PCD. In support of these in vitro findings, TDAG51 expression was increased and correlated with PCD in the atherosclerotic lesions from apoE ؊/؊ mice fed hyperhomocysteinemic diets, compared with mice fed a control diet. Collectively, these findings provide evidence that TDAG51 is induced by homocysteine, promotes detachment-mediated PCD, and contributes to the development of atherosclerosis observed in hyperhomocysteinemia.

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Section: Discussionmentioning

confidence: 99%

TDAG51 Is Induced by Homocysteine, Promotes Detachment-mediated Programmed Cell Death, and Contributes to the Development of Atherosclerosis in Hyperhomocysteinemia

Hossain

Thienen

Werstuck

et al. 2003

Journal of Biological Chemistry

210

194

View full text Add to dashboard Cite

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“…The results of some in vivo experiments in humans add further credence to the concept that elevated tHcy may provoke an acute vascular lesion. The acute hyperhomocysteinemia after methionine loading is associated with acute endothelemia (113), an increase in soluble adhesion molecules, increments of several coagulation variables, and impaired hemodynamic and rheologic responses to L-arginine (114).…”

Section: Plausible Mechanismsmentioning

confidence: 99%

The controversy over homocysteine and cardiovascular risk

Ueland

Refsum

Beresford

et al. 2000

The American Journal of Clinical Nutrition

453

237

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Elevated plasma total homocysteine (tHcy) is a risk factor for occlusive cardiovascular disease (CVD). This concept is based on the observations of premature vascular disease in patients with homocystinuria, the relation between tHcy and both clinical CVD as well as preclinical atherosclerotic disease, the relation between tHcy in children and CVD in their parents or relatives, and reduction in CVD or surrogate endpoints after tHcy-lowering intervention with B vitamins. Plausible mechanisms include the in vivo interference with nitric oxide-dependent reactive vasodilatation. Some observations have raised questions about tHcy as a risk factor. 1) Some prospective studies showed a weak relation or no relation between tHcy and CVD. 2) Several traditional risk factors are associated with tHcy and may confound the relation between tHcy and CVD. 3) tHcy is related to renal function, and hyperhomocysteinemia may reflect early nephrosclerosis. 4) The C677T transition of the methylenetetrahydrofolate reductase gene causes a moderate increase in tHcy but no or only minor increased CVD risk. However, the strength of some of these arguments can be questioned because there is increasing evidence that tHcy is a proximate risk factor provoking the acute event, it strongly interacts with traditional risk factors, and it may predict CVD or death in patients with chronic renal failure. Furthermore, the studies of the C677T polymorphism lack statistical power, and the TT genotype may even modulate CVD risk independently of homocysteine. Thus, only placebocontrolled intervention studies with tHcy-lowering B vitamins and clinical endpoints can provide additional valid arguments for the debate over whether tHcy is a causal CVD risk factor. Am J Clin Nutr 2000;72:324-32.KEY WORDS Homocysteine, cardiovascular disease, methylenetetrahydrofolate reductase polymorphism, renal, nephrosclerosis INTRODUCTIONPatients with the inborn metabolic error homocystinuria have markedly elevated homocysteine concentrations in plasma and urine and occlusive vascular disease in early adulthood or even in childhood (1). On the basis of these observations, McCully (2) formulated the homocysteine theory of atherosclerosis in 1969 (2). In 1976, Wilcken and Wilcken (3) published their pioneering work on abnormal homocysteine metabolism in patients with coronary artery disease. Since then, convincing evidence has been gathered on the relation between moderate elevation of plasma total homocysteine (tHcy) and the risk of occlusive vascular disease in the coronary, cerebral (4), and peripheral arteries and, more recently, of venous thrombosis (5-7). The literature on this subject now includes > 120 articles reporting on > 12 000 patient-control subject sets. Almost all of the retrospective case-control studies and most of the prospective studies support the concept of hyperhomocysteinemia as a risk factor for cardiovascular disease (CVD; 6, 8), and several meta-analyses showed similar, consistent results, as summarized in Figure 1.Some observations may s...

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“…On the basis of morphology, intact nucleated cells were recovered in leukoconcentrates by Bouvier et al [4] whereas anuclear "carcasses" were detected in platelet rich plasma by Hladovec [5]. Several authors subsequently described similar cells in different models of endothelial damage such as shock by E. Coli endotoxin in animals [6], or smoking, acute myocardial infarction, immunosuppression, hypertension and homocysteinaemia in man [7][8][9][10][11]. However, divergent results were reported by these groups, due to the variety of cell fractions studied, cell identification by morphology, and methods of cells concentration, based on physical properties such as size or density.…”

Section: Circulating Endothelial Cells: From the Concept Of Rare Evenmentioning

confidence: 99%