Disturbed ratio of erythrocyte and plasma S-adenosylmethionine/S-adenosylhomocysteine in peripheral arterial occlusive disease

Loehrer, F.; Tschöpl, Martin; Angst, Christian P.; Litynski, Piotr; Jäger, K; Fowler, Brian; Haefeli, Walter E.

doi:10.1016/s0021-9150(00)00449-4

Cited by 66 publications

(50 citation statements)

References 36 publications

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“…Furthermore, short-term exposure to high Hcy concentrations may reflect a prolonged exposure to moderately elevated Hcy concentrations as occur lifelong in patients. The SAH concentrations that we measured after incubation with ADA and Hcy, however, are comparable to the concentrations found intracellular in erythrocytes of cardiovascular patients [33]. Another limitation of the present study is that it was not possible to determine the intracellular concentration of Hcy since very few laboratories are able to measure this.…”

Section: Discussionsupporting

confidence: 49%

Homocysteine-induced cardiomyocyte apoptosis and plasma membrane flip-flop are independent of S-adenosylhomocysteine: a crucial role for nuclear p47phox

et al. 2011

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We previously found that homocysteine (Hcy) induced plasma membrane flip-flop, apoptosis, and necrosis in cardiomyocytes. Inactivation of flippase by Hcy induced membrane flip-flop, while apoptosis was induced via a NOX2-dependent mechanism. It has been suggested that S-adenosylhomocysteine (SAH) is the main causative factor in hyperhomocysteinemia (HHC)-induced pathogenesis of cardiovascular disease. Therefore, we evaluated whether the observed cytotoxic effect of Hcy in cardiomyocytes is SAH dependent. Rat cardiomyoblasts (H9c2 cells) were treated under different conditions: (1) nontreated control (1.5 nM intracellular SAH with 2.8 lM extracellular L-Hcy), (2) incubation with 50 lM adenosine-2,3-dialdehyde (ADA resulting in 83.5 nM intracellular SAH, and 1.6 lM extracellular L-Hcy), (3) incubation with 2.5 mM D,L-Hcy (resulting in 68 nM intracellular SAH and 1513 lM extracellular L-Hcy) with or without 10 lM reactive oxygen species (ROS)-inhibitor apocynin, and (4) incubation with 100 nM, 10 lM, and 100 lM SAH. We then determined the effect on annexin V/propodium iodide positivity, flippase activity, caspase-3 activity, intracellular NOX2 and p47 phox expression and localization, and nuclear ROS production. In contrast to Hcy, ADA did not induce apoptosis, necrosis, or membrane flip-flop. Remarkably, both ADA and Hcy induced a significant increase in nuclear NOX2 expression. However, in contrast to ADA, Hcy additionally induced nuclear p47 phox expression, increased nuclear ROS production, and inactivated flippase. Incubation with SAH did not have an effect on cell viability, nor on flippase activity, nor on nuclear NOX2-, p47phox expression or nuclear ROS production. HHCinduced membrane flip-flop and apoptosis in cardiomyocytes is due to increased Hcy levels and not primarily related to increased intracellular SAH, which plays a Jessica A. Sipkens and Paul A. J. Krijnen contributed equally to this manuscript.

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Section: Discussionsupporting

confidence: 49%

Homocysteine-induced cardiomyocyte apoptosis and plasma membrane flip-flop are independent of S-adenosylhomocysteine: a crucial role for nuclear p47phox

et al. 2011

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“…However, in vivo studies showed that increased Hcy is associated with elevated plasma AdoHcy levels (56) and that AdoHcy rather than Hcy contributes to cardiovascular disease (16,57). Accordingly, AdoHcy but not homocysteine itself is toxic to yeast cells compromised in homocysteine metabolism through the trans-sulfuration pathway (58).…”

Section: Discussionmentioning

confidence: 99%

S-Adenosyl-L-homocysteine Hydrolase, Key Enzyme of Methylation Metabolism, Regulates Phosphatidylcholine Synthesis and Triacylglycerol Homeostasis in Yeast

Malanovic

Streith

Wolinski

et al. 2008

Journal of Biological Chemistry

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In eukaryotes, S-adenosyl-L-homocysteine hydrolase (Sah1) offers a single way for degradation of S-adenosyl-L-homocysteine, a product and potent competitive inhibitor of S-adenosyl-L-methionine (AdoMet)-dependent methyltransferases. De novophosphatidylcholine(PC)synthesisrequiresthreeAdoMetdependent methylation steps. Here we show that down-regulation of SAH1 expression in yeast leads to accumulation of S-adenosyl-L-homocysteine and decreased de novo PC synthesis in vivo. This decrease is accompanied by an increase in triacylglycerol (TG) levels, demonstrating that Sah1-regulated methylation has a major impact on cellular lipid homeostasis. TG accumulation is also observed in cho2 and opi3 mutants defective in methylation of phosphatidylethanolamine to PC, confirming that PC de novo synthesis and TG synthesis are metabolically coupled through the efficiency of the phospholipid methylation reaction. Indeed, because both types of lipids share phosphatidic acid as a precursor, we find in cells with down-regulated Sah1 activity major alterations in the expression of the INO1 gene as well as in the localization of Opi1, a negative regulatory factor of phospholipid synthesis, which binds and is retained in the endoplasmic reticulum membrane by phosphatidic acid in conjunction with VAMP/ synaptobrevin-associated protein, Scs2. The addition of homocysteine, by the reversal of the Sah1-catalyzed reaction, also leads to TG accumulation in yeast, providing an attractive model for the role of homocysteine as a risk factor of atherosclerosis in humans.

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“…These might include (i) inhibitions of additional methyltransferases; (ii) adverse effects of abnormally high concentrations of AdoMet and AdoHcy and͞or the abnormally low ratio of AdoMet͞AdoHcy on vascular endothelium and other cells (41)(42)(43)(44)(45); (iii) adenosine depletion due to inadequate cleavage of AdoHcy, which might result in renal dysfunction (46), although glomerular and tubular function were normal in our patient; (iv) disturbed copper metabolism based on the finding that AdoHcy hydrolase is an important copper binding protein (47,48), although the normal serum copper and ceruloplasmin levels in our patient and his clinical presentation do not suggest disturbed copper metabolism; and (v) glutathione depletion consequent to impaired conversion of methionine to cysteine, the metabolic precursor of glutathione. In turn, glutathione depletion may result in vulnerability to oxidative stress and xenobiotic toxicities, which could lead to liver dysfunction (20).…”

Section: Distribution Of Pathologic Process and Pathophysiological Comentioning

confidence: 99%

S -adenosylhomocysteine hydrolase deficiency in a human: A genetic disorder of methionine metabolism

Barić

Fumić

Glenn

et al. 2004

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

205

226

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We report studies of a Croatian boy, a proven case of human S-adenosylhomocysteine (AdoHcy) hydrolase deficiency. Psychomotor development was slow until his fifth month; thereafter, virtually absent until treatment was started. He had marked hypotonia with elevated serum creatine kinase and transaminases, prolonged prothrombin time and low albumin. Electron microscopy of muscle showed numerous abnormal myelin figures; liver biopsy showed mild hepatitis with sparse rough endoplasmic reticulum. Brain MRI at 12.7 months revealed white matter atrophy and abnormally slow myelination. Hypermethioninemia was present in the initial metabolic study at age 8 months, and persisted (up to 784 M) without tyrosine elevation. Plasma total homocysteine was very slightly elevated for an infant to 14.5-15.9 M. In plasma, S-adenosylmethionine was 30-fold and AdoHcy 150-fold elevated. Activity of AdoHcy hydrolase was Ϸ3% of control in liver and was 5-10% of the control values in red blood cells and cultured fibroblasts. We found no evidence of a soluble inhibitor of the enzyme in extracts of the patient's cultured fibroblasts. Additional pretreatment abnormalities in plasma included low concentrations of phosphatidylcholine and choline, with elevations of guanidinoacetate, betaine, dimethylglycine, and cystathionine. Leukocyte DNA was hypermethylated. Gene analysis revealed two mutations in exon 4: a maternally derived stop codon, and a paternally derived missense mutation. We discuss reasons for biochemical abnormalities and pathophysiological aspects of AdoHcy hydrolase deficiency.

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Disturbed ratio of erythrocyte and plasma S-adenosylmethionine/S-adenosylhomocysteine in peripheral arterial occlusive disease

Cited by 66 publications

References 36 publications

Homocysteine-induced cardiomyocyte apoptosis and plasma membrane flip-flop are independent of S-adenosylhomocysteine: a crucial role for nuclear p47phox

Homocysteine-induced cardiomyocyte apoptosis and plasma membrane flip-flop are independent of S-adenosylhomocysteine: a crucial role for nuclear p47phox

S-Adenosyl-L-homocysteine Hydrolase, Key Enzyme of Methylation Metabolism, Regulates Phosphatidylcholine Synthesis and Triacylglycerol Homeostasis in Yeast

S -adenosylhomocysteine hydrolase deficiency in a human: A genetic disorder of methionine metabolism

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