NDLI: Intracellular S-adenosylhomocysteine increased levels are associated with DNA hypomethylation in HUVEC

Content Provider	Springer Nature Link
Author	Castro, Rita Rivera, Isabel Martins, Carla Struys, Eduard A. Jansen, Erwin E. W. Clode, Nu Graça, Luís M. Blom, Henk J. Jakobs, Cornelis Tavares de Almeida, Isabel
Copyright Year	2005
Abstract	Hyperhomocysteinemia is a risk factor for atherosclerosis and vascular disease; however, the mechanism underlying this association remains poorly understood. Increased levels of intracellular S-adenosylhomocysteine (AdoHcy), secondary to homocysteine-mediated reversal of the AdoHcy hydrolase reaction, have been associated with reduced DNA methylation patterns and pointed as responsible for the hyperhomocysteinemia-related endothelial dysfunction. Methylation is an epigenetic feature of genomic DNA, which leads to alterations in gene expression. So far, the effect of intracellular AdoHcy accumulation on DNA methylation patterns has not yet been fully substantiated by experimental evidence. The present study was designed to evaluate, in cultured endothelial cells, the effect of AdoHcy accumulation on genomic global DNA methylation status. Experimental intracellular accumulation of AdoHcy was induced by adenosine-2,3-dialdehyde (ADA), an inhibitor of AdoHcy hydrolase. Increased concentrations of inhibitor were tested, and unsupplemented medium incubations were used as controls. Cytosolic and nuclear fractions were obtained from trypsinized cells after 72 h of incubation. Total homocysteine concentration was quantified (culture medium and cytosolic fractions) by high-performance liquid chromatography (HPLC). S-Adenosylmethionine and AdoHcy concentrations were measured (cytosolic fractions) by stable-isotope dilution LC-tandem mass spectrometry method. Genomic DNA was obtained from the nuclear fraction, and global DNA methylation status was evaluated by the cytosine extension assay. The results showed that supplementation of the culture medium with ADA had no cytotoxic effect and increased the intracellular AdoHcy concentration in a dose-dependent manner. A significant negative correlation was observed between intracellular AdoHcy and genomic DNA methylation status. These findings strongly point to the importance of AdoHcy as a pivotal biomarker of genomic DNA methylation status.
Starting Page	831
Ending Page	836
Page Count	6
File Format	PDF
ISSN	09462716
Journal	Journal of Molecular Medicine
Volume Number	83
Issue Number	10
e-ISSN	14321440
Language	English
Publisher	Springer-Verlag
Publisher Date	2005-06-23
Publisher Place	Berlin/Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Molecular Medicine Genetics (clinical)

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