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Folinic Acid Increases Protein Arginine Methylation in Human Endothelial Cells

1
Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal
2
Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
3
Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118, USA
4
Department of Physiology, VU University Medical Center, 1081 HV Amsterdam, The Netherlands
5
Laboratory for Clinical Biochemistry and Metabolism, Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine University Hospital, Mathildenstrasse 1, D-79106 Freiburg, Germany
6
Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal
7
Department of Nutritional Sciences, Pennsylvania State University, University Park, 16802 PA, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Nutrients 2018, 10(4), 404; https://doi.org/10.3390/nu10040404
Received: 6 January 2018 / Revised: 10 March 2018 / Accepted: 22 March 2018 / Published: 24 March 2018
Elevated plasma total homocysteine (tHcy) is associated with increased risk of cardiovascular disease, but the mechanisms underlying this association are not completely understood. Cellular hypomethylation has been suggested to be a key pathophysiologic mechanism, since S-adenosylhomocysteine (AdoHcy), the Hcy metabolic precursor and a potent inhibitor of methyltransferase activity, accumulates in the setting of hyperhomocysteinemia. In this study, the impact of folate and methionine on intracellular AdoHcy levels and protein arginine methylation status was studied. Human endothelial cells were incubated with increasing concentrations of folinic acid (FnA), a stable precursor of folate, with or without methionine restriction. The levels of intracellular AdoHcy and AdoMet, tHcy in the cell culture medium, and protein-incorporated methylarginines were evaluated by suitable liquid chromatography techniques. FnA supplementation, with or without methionine restriction, reduced the level of tHcy and did not affect intracellular AdoMet levels. Interestingly, FnA supplementation reduced intracellular AdoHcy levels only in cells grown under methionine restriction. Furthermore, these cells also displayed increased protein arginine methylation status. These observations suggest that folic acid supplementation may enhance cellular methylation capacity under a low methionine status. Our results lead us to hypothesize that the putative benefits of folic acid supplementation in restoring endothelial homeostasis, thus preventing atherothrombotic events, should be reevaluated in subjects under a methionine restriction diet. View Full-Text
Keywords: folate; homocysteine; cellular methylation capacity; protein arginine methylation folate; homocysteine; cellular methylation capacity; protein arginine methylation
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Esse, R.; Teerlink, T.; Koolwijk, P.; Tavares de Almeida, I.; Blom, H.J.; Castro, R. Folinic Acid Increases Protein Arginine Methylation in Human Endothelial Cells. Nutrients 2018, 10, 404.

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