Inhibition of cellular methyltransferases promotes endothelial cell activation by suppressing glutathione peroxidase 1 protein expression

J Biol Chem. 2014 May 30;289(22):15350-62. doi: 10.1074/jbc.M114.549782. Epub 2014 Apr 9.

Abstract

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 tRNA(Sec) to the Um34 form. The formation of methylated tRNA(Sec) 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 tRNA(Sec) 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 proinflammatory activation of endothelial cells characterized by up-regulation of adhesion molecules and an augmented capacity to bind leukocytes. Taken together, these data suggest that SAH accumulation in endothelial cells can induce tRNA(Sec) hypomethylation, which alters the expression of selenoproteins such as GPx-1 to contribute to a proatherogenic endothelial phenotype.

Keywords: Cell Adhesion; Endothelial Cell; Glutathione Peroxidase; Oxidative Stress; S-Adenosylhomocysteine; Selenoprotein; tRNA Methylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Adhesion / physiology
  • Endothelial Cells / drug effects
  • Endothelial Cells / enzymology*
  • Glutathione Peroxidase / genetics*
  • Glutathione Peroxidase / metabolism*
  • Homocysteine / metabolism
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Hydrogen Peroxide / metabolism
  • Leukocytes / cytology
  • Methylation
  • Methyltransferases / metabolism*
  • Oxidative Stress / physiology
  • RNA, Transfer, Amino Acyl / metabolism*
  • RNA, Transfer, Ser / metabolism
  • S-Adenosylhomocysteine / metabolism*
  • S-Adenosylmethionine / metabolism
  • Selenium / pharmacology
  • Selenoproteins / metabolism

Substances

  • RNA, Transfer, Amino Acyl
  • RNA, Transfer, Ser
  • Selenoproteins
  • selenocysteinyl-tRNA
  • Homocysteine
  • S-Adenosylmethionine
  • S-Adenosylhomocysteine
  • Hydrogen Peroxide
  • glutathione peroxidase GPX1
  • Glutathione Peroxidase
  • Methyltransferases
  • Selenium