Inhibition of Cellular Methyltransferases Promotes Endothelial Cell Activation by Suppressing Glutathione Peroxidase-1 Expression [RNA]

April 9th, 2014 by Barroso, M., Florindo, C., Kalwa, H., Silva, Z., Turanov, A. A., Carlson, B. A., Tavares de Almeida, I., Blom, H. J., Gladyshev, V. N., Hatfield, D. L., Michel, T., Castro, R., Loscalzo, J., Handy, D. E.

S-adenosylhomocysteine (SAH) is a negative regulator of most methyltransferases and the precursor for the cardiovascular risk factor homocysteine. We have previously identified a link between the homocysteine-induced suppression of the selenoprotein glutathione peroxidase-1 (GPx-1) and endothelial dysfunction. Here, we demonstrate a specific mechanism by which hypomethylation, promoted by the accumulation of the homocysteine precursor SAH, suppresses GPx-1 expression and leads to inflammatory activation of endothelial cells. The expression of GPx-1 and a subset of other selenoproteins is dependent on the methylation of the tRNASec to the Um34 form; the formation of methylated tRNASec facilitates translational incorporation of selenocysteine at a UGA codon. Our findings demonstrate that SAH accumulation in endothelial cells suppresses the expression of GPx-1 to promote oxidative stress. Hypomethylation stress, caused by SAH accumulation, inhibits the formation of the methylated isoform of the tRNASec and reduces GPx-1 expression. In contrast, under these conditions, the expression and activity of thioredoxin reductase-1, another selenoprotein, is increased. Furthermore, SAH-induced oxidative stress creates a pro-inflammatory activation of endothelial cells characterized by upregulation of adhesion molecules and an augmented capacity to bind leukocytes. Taken together, these data suggest that SAH accumulation in endothelial cells can induce tRNASec hypomethylation which alters the expression of selenoproteins, such as GPx-1, to contribute to a pro-atherogenic endothelial phenotype.