Cellular hypomethylation is associated with impaired nitric oxide production by cultured human endothelial cells
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Cellular hypomethylation is associated with impaired nitric oxide production by cultured human endothelial cells. / Barroso, M; Rocha, Monica S; Esse, Ruben; Gonçalves, I; Gomes, A Q; Teerlink, Tom; Jakobs, C; Blom, Henk J; Loscalzo, Joseph; Rivera, Isabel; de Almeida, I Tavares; Castro, Rita.
In: AMINO ACIDS, Vol. 42, No. 5, 05.2012, p. 1903-11.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Cellular hypomethylation is associated with impaired nitric oxide production by cultured human endothelial cells
AU - Barroso, M
AU - Rocha, Monica S
AU - Esse, Ruben
AU - Gonçalves, I
AU - Gomes, A Q
AU - Teerlink, Tom
AU - Jakobs, C
AU - Blom, Henk J
AU - Loscalzo, Joseph
AU - Rivera, Isabel
AU - de Almeida, I Tavares
AU - Castro, Rita
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.
KW - Arginine
KW - Cells, Cultured
KW - Endothelial Cells
KW - Gene Expression Regulation
KW - Human Umbilical Vein Endothelial Cells
KW - Humans
KW - Hyperhomocysteinemia
KW - Methylation
KW - Nitric Oxide
KW - Nitric Oxide Synthase Type III
KW - S-Adenosylhomocysteine
KW - Vascular Diseases
KW - Journal Article
KW - Research Support, N.I.H., Extramural
KW - Research Support, Non-U.S. Gov't
U2 - 10.1007/s00726-011-0916-0
DO - 10.1007/s00726-011-0916-0
M3 - SCORING: Journal article
C2 - 21614558
VL - 42
SP - 1903
EP - 1911
JO - AMINO ACIDS
JF - AMINO ACIDS
SN - 0939-4451
IS - 5
ER -