SEARCH:   Advanced

Blood, 29 January 2009, Vol. 113, No. 5, pp. 1129-1138. Prepublished online as a Blood First Edition Paper on October 22, 2008; DOI 10.1182/blood-2008-07-169821. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-07-169821v1 113/5/1129    most recent Alert me when this article is cited 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 Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Patel, N. Articles by Kalra, V. K. Search for Related Content PubMed PubMed Citation Articles by Patel, N. Articles by Kalra, V. K. Related Collections Red Cells, Iron, and Erythropoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS, IRON, AND ERYTHROPOIESIS Placenta growth factor induces 5-lipoxygenase–activating protein to increase leukotriene formation in sickle cell disease Nitin Patel1, Caryn S. Gonsalves1, Minyang Yang2, Punam Malik2,*, and Vijay K. Kalra1,* 1 Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles; and 2 Division of Hematology, Cincinnati Children's Hospital Medical Center, OH Individuals with sickle cell disease (SCD) have increased inflammation, a high incidence of airway hyperreactivity (AH), and increased circulating leukotrienes (LT). We show that expression of 5-lipoxygenase and 5-lipoxygenase activating protein (FLAP), key catalytic molecules in the LT pathway, were significantly increased in peripheral blood mononuclear cells (MNCs) in patients with SCD, compared with healthy controls. Placenta growth factor (PlGF), elaborated from erythroid cells, activated MNC and THP-1 monocytic cells to induce LT production. PlGF-mediated increased FLAP mRNA expression occurred via activation of phosphoinositide-3 (PI-3) kinase, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and hypoxia inducible factor-1 (HIF-1). HIF-1 small interfering RNA (siRNA) reduced PlGF-induced FLAP expression. FLAP promoter-driven luciferase constructs demonstrated that PlGF-mediated luciferase induction was abrogated upon mutation of HIF-1 response element (HRE), but not the nuclear factor-B (NF-B) site in the FLAP promoter; a finding confirmed by chromatin immunoprecipitation (ChIP) analysis. PlGF also increased HIF-1 binding to the HRE in the FLAP promoter. Therefore, it is likely that the intrinsically elevated levels of PlGF in SCD subjects contribute to increased LT, which in turn, mediate both inflammation and AH. Herein, we identify a mechanism of increased LT in SCD and show HIF-1 as a hypoxia-independent target of PlGF. These studies provide new avenues to ameliorate these complications. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2009 by American Society of Hematology         Online ISSN: 1528-0020