Inhibition of cellular methyltransferases promotes endothelial cell activation by suppressing glutathione peroxidase 1 protein expression.
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.
From the Cardiovascular and the Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL) and.
Madalena
M
Barroso
the Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL) and.
Cristina
C
Florindo
From the Cardiovascular and.
Hermann
H
Kalwa
the Chronic Diseases Research Center, Departamento de Imunologia, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1099-085 Lisbon, Portugal.
Zélia
Z
Silva
Genetics Divisions, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Anton A
AA
Turanov
the Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, and.
Bradley A
BA
Carlson
the Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL) and Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, 1649-004 Lisbon, Portugal.
Isabel Tavares
IT
de Almeida
the Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine, University Hospital, 79106 Freiburg, Germany.
Henk J
HJ
Blom
Genetics Divisions, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.
Vadim N
VN
Gladyshev
the Molecular Biology of Selenium Section, Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, and.
Dolph L
DL
Hatfield
From the Cardiovascular and.
Thomas
T
Michel
the Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL) and Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, 1649-004 Lisbon, Portugal.
Rita
R
Castro
From the Cardiovascular and.
Joseph
J
Loscalzo
From the Cardiovascular and dhandy@rics.bwh.harvard.edu.
Diane E
DE
Handy
D002448:Cell Adhesion / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism*; D006710:Homocysteine / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D012346:RNA, Transfer, Amino Acyl / Q000378:metabolism*; D012362:RNA, Transfer, Ser / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism; D012643:Selenium / Q000494:pharmacology; D051140:Selenoproteins / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
D012346:RNA, Transfer, Amino Acyl; D012362:RNA, Transfer, Ser; D051140:Selenoproteins; C112705:selenocysteinyl-tRNA; D006710:Homocysteine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D008780:Methyltransferases; D012643:Selenium; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human
Cell Adhesion; Endothelial Cell; Glutathione Peroxidase; Oxidative Stress; S-Adenosylhomocysteine; Selenoprotein; tRNA Methylation