TY - JOUR
T1 - Cellular hypomethylation is associated with impaired nitric oxide production by cultured human endothelial cells
AU - Barroso, M.
AU - Rocha, M. S.
AU - Esse, R.
AU - Gonçalves, I.
AU - Gomes, A. Q.
AU - Teerlink, T.
AU - Jakobs, C.
AU - Blom, H. J.
AU - Loscalzo, J.
AU - Rivera, I.
AU - De Almeida, I. Tavares
AU - Castro, R.
N1 - Funding Information:
We thank Diane E.Handy and Jane A.Leopold for scientific advice. We also thank Scott R.Oldebeken, Desiree E.C.Smith and Sigrid de Jong for theirs excellent technical assistance. This work was partially supported by the FCT (Fundação para a Ciência e Tecnologia) [PTDC/SAUGMG/68714/2006 and SFRH/BSAB/921/2009 (R.C), SFRH/BD/41970/2007 (M.R), SFRH/BD/48585/2008 (R.E)] and Fundação Calouste Gulbenkian [Grant 105783/2009 (R.C)], and by NIH Grants HL61795, HL81587, HL70819, and HL48743 (J.L).
PY - 2012/5
Y1 - 2012/5
N2 - Hyperhomocysteinemia (HHcy) is a risk factor for vascular disease, but the underlying mechanisms remain incompletely defined. Reduced bioavailability of nitric oxide (NO) is a principal manifestation of underlying endothelial dysfunction, which is an initial event in vascular disease. Inhibition of cellular methylation reactions by S-adenosylhomocysteine (AdoHcy), which accumulates during HHcy, has been suggested to contribute to vascular dysfunction. However, thus far, the effect of intracellular AdoHcy accumulation on NO bioavailability has not yet been fully substantiated by experimental evidence. The present study was carried out to evaluate whether disturbances in cellular methylation status affect NO production by cultured human endothelial cells. Here, we show that a hypomethylating environment, induced by the accumulation of AdoHcy, impairs NO production. Consistent with this finding, we observed decreased eNOS expression and activity, but, by contrast, enhanced NOS3 transcription. Taken together, our data support the existence of regulatory post-transcriptional mechanisms modulated by cellular methylation potential leading to impaired NO production by cultured human endothelial cells. As such, our conclusions may have implications for the HHcy-mediated reductions in NO bioavailability and endothelial dysfunction.
AB - Hyperhomocysteinemia (HHcy) is a risk factor for vascular disease, but the underlying mechanisms remain incompletely defined. Reduced bioavailability of nitric oxide (NO) is a principal manifestation of underlying endothelial dysfunction, which is an initial event in vascular disease. Inhibition of cellular methylation reactions by S-adenosylhomocysteine (AdoHcy), which accumulates during HHcy, has been suggested to contribute to vascular dysfunction. However, thus far, the effect of intracellular AdoHcy accumulation on NO bioavailability has not yet been fully substantiated by experimental evidence. The present study was carried out to evaluate whether disturbances in cellular methylation status affect NO production by cultured human endothelial cells. Here, we show that a hypomethylating environment, induced by the accumulation of AdoHcy, impairs NO production. Consistent with this finding, we observed decreased eNOS expression and activity, but, by contrast, enhanced NOS3 transcription. Taken together, our data support the existence of regulatory post-transcriptional mechanisms modulated by cellular methylation potential leading to impaired NO production by cultured human endothelial cells. As such, our conclusions may have implications for the HHcy-mediated reductions in NO bioavailability and endothelial dysfunction.
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U2 - 10.1007/s00726-011-0916-0
DO - 10.1007/s00726-011-0916-0
M3 - Article
C2 - 21614558
AN - SCOPUS:84862768905
SN - 0939-4451
VL - 42
SP - 1903
EP - 1911
JO - Amino Acids
JF - Amino Acids
IS - 5
ER -