Global protein and histone arginine methylation are affected in a tissue-specific manner in a rat model of diet-induced hyperhomocysteinemia |
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Authors: | Ruben Esse Cristina Florindo Apolline Imbard Mónica S Rocha An S de Vriese Yvo M Smulders Tom Teerlink Isabel Tavares de Almeida Rita Castro Henk J Blom |
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Institution: | 1. Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, 1081 HV Amsterdam, The Netherlands;2. Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal;3. Service de Biochimie-Hormonologie, Hôpital Robert Debré, APHP, 75019 Paris, France;4. Renal Unit, Department of Internal Medicine, AZ Sint-Jan AV, 8000 Bruges, Belgium;5. Department of Internal Medicine, VU University Medical Center, 1081 HV Amsterdam, The Netherlands;6. Institute for Cardiovascular Research ICaR-VU, VU University Medical Center, 1081 HV Amsterdam, The Netherlands;7. Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, 1649-003 Lisbon, Portugal |
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Abstract: | Accumulation of S-adenosylhomocysteine (AdoHcy), the homocysteine (Hcy) precursor and a potent methyltransferase inhibitor, may mediate the neurological and vascular complications associated with elevated Hcy. Protein arginine methylation is a crucial post-translational modification and generates monomethylarginine (MMA) and dimethylarginine (asymmetric, ADMA, and symmetric, SDMA) residues. We aimed at determining whether protein arginine methylation status is disturbed in an animal model of diet-induced hyperhomocysteinemia (HHcy). HHcy was achieved by dietary manipulation of Wistar rats: methionine-enrichment (HM), B vitamins deficiency (LV), or both (HMLV). Total Hcy, S-adenosylmethionine (AdoMet), AdoHcy, MMA, ADMA and SDMA concentrations in plasma or tissues (heart, brain and liver) were determined by adequate high-performance liquid chromatography or liquid chromatography-electrospray ionization-tandem mass spectrometry methods. Moreover, in tissues from the HMLV group, histone arginine asymmetric dimethylation was evaluated by Western blotting, and the histone methylation marks H3R17me2a, H3R8me2a and H4R3me2a were studied. HHcy was induced by all special diets, with elevation of AdoHcy concentrations in liver (LV and HMLV) and heart (HMLV) (all versus control). Plasma ADMA levels were lower in all hyperhomocysteinemic animals. Protein-incorporated ADMA levels were decreased in brain and in heart (both for the LV and HMLV groups). Moreover, in brain of animals exposed to the HMLV diet, the H3R8me2a mark was profoundly decreased. In conclusion, our results show that diet-induced Hcy elevation disturbs global protein arginine methylation in a tissue-specific manner and affects histone arginine methylation in brain. Future research is warranted to disclose the functional implications of the global protein and histone arginine hypomethylation triggered by Hcy elevation. |
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