TY - JOUR
T1 - Global protein and histone arginine methylation are affected in a tissue-specific manner in a rat model of diet-induced hyperhomocysteinemia
AU - Esse, Ruben
AU - Florindo, Cristina
AU - Imbard, Apolline
AU - Rocha, Mónica S.
AU - De Vriese, An S.
AU - Smulders, Yvo M.
AU - Teerlink, Tom
AU - Tavares de Almeida, Isabel
AU - Castro, Rita
AU - Blom, Henk J.
N1 - Funding Information:
This work was financially supported by the Fundação para a Ciência e a Tecnologia, Portugal [grants PTDC/SAU-ORG/112683/2009 , SFRH/BD/48585/2008 and SFRH/BD/41970/2007 ]. Fundação para a Ciência e a Tecnologia had no involvement in the design of the study, collection, analysis and interpretation of the data, writing of the report and decision to submit the article for publication.
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84879581743&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84879581743&partnerID=8YFLogxK
U2 - 10.1016/j.bbadis.2013.05.013
DO - 10.1016/j.bbadis.2013.05.013
M3 - Article
C2 - 23707560
AN - SCOPUS:84879581743
VL - 1832
SP - 1708
EP - 1714
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
SN - 0925-4439
IS - 10
ER -