Published online before print February 28, 2008, doi: 10.1161/CIRCRESAHA.108.171082
© 2008 American Heart Association, Inc.
Molecular Medicine |
Homocysteine Inhibits Arterial Endothelial Cell Growth Through Transcriptional Downregulation of Fibroblast Growth Factor-2 Involving G Protein and DNA Methylation
From the Departments of Internal Medicine (P.-Y.C., C.-M.L., Y.-T.L.) and Biochemistry and Molecular Biology (S.-C.L., Y.-J.C., W.-H.H.), National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei; Graduate Institute of Cell and Molecular Biology (S.-F.C.), Taipei Medical University, Taipei; the Department of Biochemistry and Molecular Biology (W.S.L.L.), Program in Genes and Development, University of Texas M.D. Anderson Cancer Center, Houston; and the Department of Medicine (T.A.D., C.-H.C.), Baylor College of Medicine, Houston, Tex.
Correspondence to Yuan-Teh Lee, MD, PhD, No. 7, Chung-Shan South Rd, Taipei 100, Taiwan. E-mail ytlee{at}ha.mc.ntu.edu.tw
Homocysteine (Hcy) contributes to atherogenesis and angiostasis by altering the phenotype of arterial endothelial cells (ECs). The present study was aimed at elucidating potential mechanisms by which Hcy can slow EC proliferation and induce EC apoptosis, thereby disrupting endothelial integrity. Given the strong mitogenic and antiapoptotic properties of fibroblast growth factor (FGF)2, we examined whether Hcy can modulate its expression. In cultured human coronary and bovine aortic ECs, Hcy exerted time- and concentration-dependent (0 to 500 µmol/L) reduction of the mRNA and protein levels of FGF2, whereas vascular endothelial growth factor expression was not affected until Hcy reached a proapoptotic 500 µmol/L. By testing a panel of signal transduction inhibitors, we found that the Hcy-induced downregulation of FGF2 was specifically attenuated by pertussis toxin, an inhibitor of Gi protein signaling. Hcy induced cell cycle arrest at the G1/S transition and increased TUNEL-positive apoptotic cells in a graded manner. These effects were effectively counteracted by exogenous FGF2. Reporter gene assays showed that Hcy downregulated FGF2 by transcriptional repression of the gene promoter encompassed in a CpG dinucleotide-rich island. This region was heavily methylated at the cytosine residues by Hcy despite decreased methylation potential (S-adenosylmethionine to S-adenosylhomocysteine ratio). Normal levels of FGF2 transcription were restored to ECs simultaneously exposed to Hcy and 5-aza-deoxycytidine. We conclude that homocysteine disrupts the growth and survival of ECs through a G protein–mediated pathway associated with altered promoter DNA methylation and the transcriptional repression of FGF2.
Key Words: homocysteine • endothelial cells • growth factors • transcriptional regulation • DNA methylation
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Circ. Res. 2008 102: 869-870.
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