This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morimoto, M. Articles by Kita, T. Search for Related Content PubMed PubMed Citation Articles by Morimoto, M. Articles by Kita, T. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections Pathophysiology Gene regulation Lipid and lipoprotein metabolism Mechanism of atherosclerosis/growth factors

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:771.)
© 2001 American Heart Association, Inc.

Vascular Biology

Lysophosphatidylcholine Induces Early Growth Response Factor-1 Expression and Activates the Core Promoter of PDGF-A Chain in Vascular Endothelial Cells

Masafumi Morimoto; Noriaki Kume; Susumu Miyamoto; Yasushi Ueno; Hiroharu Kataoka; Manabu Minami; Kazutaka Hayashida; Nobuo Hashimoto; Toru Kita

From the Departments of Geriatric Medicine (N.K., M. Minami, K.H., T.K.) and Neurosurgery (M. Morimoto, S.M., Y.U., H.K., N.H.), Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Correspondence to Noriaki Kume, MD, PhD, Department of Geriatric Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. E-mail nkume{at}kuhp.kyoto-u.ac.jp

Abstract—Lysophosphatidylcholine (lyso-PC), a polar phospholipid that is increased in atherogenic lipoproteins and atherosclerotic lesions, has been shown to transcriptionally induce the expression of endothelial genes relevant to atherogenesis. In cultured bovine aortic endothelial cells (BAECs), we show that lyso-PC induces the expression of early growth response factor (Egr)-1 and thereby activates the proximal promoter of the platelet-derived growth factor (PDGF)-A chain located 55 to 71 bp upstream from the transcription start site, which has been shown to be crucial for PDGF-A chain expression induced by fluid shear stress and fibroblast growth factor-1. Northern blot analyses showed that lyso-PC (10 to 20 µmol/L) transiently (30 minutes to 1 hour) induced expression of Egr-1 mRNA. Induced expression of Egr-1 mRNA, which was associated with increased amounts of Egr-1 protein in nuclei, preceded PDGF-A chain mRNA induction in lyso-PC–activated BAECs. Nuclear runoff assay revealed that lyso-PC stimulates transcription of the Egr-1 gene. Transient transfection of the oligonucleotide corresponding to the proximal promoter of the PDGF-A chain (oligo A) linked to the luciferase reporter gene revealed that lyso-PC can activate the core promoter of the PDGF-A chain by 5-fold. Insertion of a guanine at 3 sites in the oligo A abolished the lyso-PC–induced increases in luciferase activities. Electrophoretic mobility shift assay with use of radiolabeled oligo A showed a lyso-PC–inducible shift band, which was suppressed by excess amounts of unlabeled oligo A or an anti–Egr-1 antibody. In addition, lyso-PC–induced Egr-1 expression was inhibited by PD98059, a specific inhibitor of mitogen-activated protein kinase kinase-1 (MEK1), suggesting that lyso–PC-induced expression of Egr-1 depends on the MEK1/extracellular signal–regulated kinase pathway. Taken together, transcriptional activation of Egr-1–dependent genes by this atherogenic lipid may be a key regulator of atherogenesis.

Key Words: early growth response factor • lysophosphatidylcholine • platelet-derived growth factor • ERK signaling pathway

This article has been cited by other articles:

				M. Takahashi, Y. Hiyama, M. Yokoyama, S. Yu, Y. Hu, K. Melford, A. Bensadoun, and I. J. Goldberg In Vivo Arterial Lipoprotein Lipase Expression Augments Inflammatory Responses and Impairs Vascular Dilatation Arterioscler. Thromb. Vasc. Biol., March 1, 2008; 28(3): 455 - 462. [Abstract] [Full Text] [PDF]

				J. L. Ingram, A. Antao-Menezes, J. B. Mangum, O. Lyght, P. J. Lee, J. A. Elias, and J. C. Bonner Opposing Actions of Stat1 and Stat6 on IL-13-Induced Up-Regulation of Early Growth Response-1 and Platelet-Derived Growth Factor Ligands in Pulmonary Fibroblasts J. Immunol., September 15, 2006; 177(6): 4141 - 4148. [Abstract] [Full Text] [PDF]

				L. M. Khachigian Early Growth Response-1 in Cardiovascular Pathobiology Circ. Res., February 3, 2006; 98(2): 186 - 191. [Abstract] [Full Text] [PDF]

				A. Md Sheikh, H. Ochi, A. Manabe, and J. Masuda Lysophosphatidylcholine posttranscriptionally inhibits interferon-{gamma}-induced IP-10, Mig and I-Tac expression in endothelial cells Cardiovasc Res, January 1, 2005; 65(1): 263 - 271. [Abstract] [Full Text] [PDF]

				H. Lum, J. Qiao, R. J. Walter, F. Huang, P. V. Subbaiah, K. S. Kim, and O. Holian Inflammatory stress increases receptor for lysophosphatidylcholine in human microvascular endothelial cells Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1786 - H1789. [Abstract] [Full Text] [PDF]

				E. Hurt-Camejo, G. Camejo, H. Peilot, K. Oorni, and P. Kovanen Phospholipase A2 in Vascular Disease Circ. Res., August 17, 2001; 89(4): 298 - 304. [Abstract] [Full Text] [PDF]