Placenta growth factor-induced early growth response 1 (Egr-1) regulates hypoxia-inducible factor-1alpha (HIF-1alpha) in endothelial cells.
Leukotrienes, the lipid inflammatory products derived from arachidonic acid, are involved in the pathogenesis of respiratory and cardiovascular diseases and reactive airway disease in sickle cell disease. Placenta growth factor (PlGF), elaborated from erythroid cells, increased the mRNA expression of 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) in human pulmonary microvascular endothelial cells. PlGF-induced both promoter activity and mRNA expression of hypoxia-inducible factor-1alpha (HIF-1alpha), which was abrogated by early growth response-1 (EGR-1) small interfering RNA. PlGF showed a temporal reciprocal relationship in the mRNA levels of EGR-1 and NAB2, the latter a repressor of Egr-1. Moreover, Nab2, but not mutant Nab2, significantly reduced promoter activity and mRNA expression of HIF-1alpha and also reduced expression of the HIF-1alpha target gene FLAP. Furthermore, overexpression of Egr-1 led to increased promoter activities for both HIF-1alpha and FLAP in the absence of PlGF. Additionally, the Egr-1-mediated induction of HIF-1alpha and FLAP promoters was reduced to basal levels by EGR-1 small interfering RNA. The binding of Egr-1 to HIF-1alpha promoter was corroborated by electrophoretic mobility shift assay and chromatin immunoprecipitation assay, which showed increased Egr-1 binding to the HIF-1alpha promoter in response to PlGF stimulation. These studies provide a novel mechanism for PlGF-mediated regulation of HIF-1alpha via Egr-1, which results in increased FLAP expression. This study provides a new therapeutic target, namely Egr-1, for attenuation of elevated leukotriene levels in patients with sickle cell disease and other inflammatory diseases.
Patel
Nitin
N
Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Kalra
Vijay K
VK
D000755:Anemia, Sickle Cell / Q000097:blood; D004277:DNA, Single-Stranded / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007249:Inflammation / Q000097:blood; D007975:Leukotriene B4 / Q000378:metabolism; D015289:Leukotrienes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D000072483:Placenta Growth Factor; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C400152:DNA enzyme ED5; D004277:DNA, Single-Stranded; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D015289:Leukotrienes; D008070:Lipopolysaccharides; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D000072483:Placenta Growth Factor; D007975:Leukotriene B4
Nat Med. 2004 Sep;10(9):966-73
15322539
Science. 1987 Sep 4;237(4819):1171-6
2820055
Biochem J. 2006 Jun 15;396(3):517-27
16533170
Blood. 2003 Aug 15;102(4):1515-24
12689930
J Biol Chem. 2003 Apr 18;278(16):13810-8
12571239
J Biol Chem. 2005 Dec 30;280(52):42785-93
16260776
J Biol Chem. 2002 Oct 11;277(41):38205-11
12149254
Pharmacol Rev. 2006 Sep;58(3):375-88
16968946
N Engl J Med. 1990 Sep 6;323(10):645-55
2166915
Nature. 2002 Jun 27;417(6892):975-8
12050673
J Biol Chem. 1985 Jan 25;260(2):1006-14
3881419
Blood. 2003 Aug 15;102(4):1506-14
12714517
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8298-303
9653181
Science. 2007 Jul 27;317(5837):510-2
17600184
J Clin Invest. 1996 Jun 1;97(11):2491-8
8647941
N Engl J Med. 2007 Nov 1;357(18):1841-54
17978293
Proc Natl Acad Sci U S A. 2009 May 19;106(20):8296-301
19416808
Am J Respir Crit Care Med. 1998 Jan;157(1):219-29
9445303
J Immunol. 2006 Nov 15;177(10):7211-24
17082639
Mol Cell Biol. 2001 May;21(10):3436-44
11313469
Science. 2001 Nov 30;294(5548):1871-5
11729303
Biochemistry. 1989 Feb 21;28(4):1755-62
2719931
J Biol Chem. 1995 Nov 17;270(46):27679-86
7499234
J Immunol. 2004 Aug 1;173(3):1503-10
15265876
Methods Mol Biol. 1999;120:119-44
10343315
J Neurovirol. 2001 Apr;7(2):125-34
11517385
Blood. 2008 Aug 1;112(3):856-65
18411415
Cancer Res. 2006 Jul 15;66(14):7067-74
16849552
Nature. 2008 Jun 5;453(7196):807-11
18432192
Am J Respir Cell Mol Biol. 1998 Aug;19(2):316-23
9698605
J Biol Chem. 1986 Dec 15;261(35):16466-72
3023351
Blood. 2002 Dec 15;100(13):4454-61
12393577
Biochem Biophys Res Commun. 1999 Aug 2;261(2):534-40
10425220
Am J Hematol. 2008 Aug;83(8):640-3
18506703
Blood. 2009 Jan 29;113(5):1129-38
18945963
Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):755-61
17272744
Mol Cell Biol. 1996 Jul;16(7):3545-53
8668170
Anal Biochem. 2009 Mar 15;386(2):251-5
19150324
J Appl Physiol (1985). 2000 Apr;88(4):1474-80
10749844
FASEB J. 2001 Jan;15(1):230-242
11149911
Biochem J. 2008 Jun 15;412(3):477-84
18393939
Biochem J. 2002 Jan 15;361(Pt 2):267-76
11772398
J Biol Chem. 2006 Jun 2;281(22):15129-37
16574654
Blood. 2004 Feb 1;103(3):1124-30
14525767
J Lipid Res. 2009 Apr;50 Suppl:S40-5
18987389
J Biol Chem. 2003 Mar 28;278(13):11433-40
12427750
J Immunol. 2003 May 15;170(10):5281-94
12734378
Nat Med. 2000 Dec;6(12):1355-61
11100120
Biochem Biophys Res Commun. 2001 May 4;283(2):480-6
11327726
Genomics. 1998 Sep 1;52(2):159-65
9782081
J Neurochem. 2004 Dec;91(5):1199-210
15569263
Am J Physiol Cell Physiol. 2005 May;288(5):C1125-33
15625306
Mol Biol Cell. 2007 Dec;18(12):4691-7
17898080
J Lab Clin Med. 2002 Feb;139(2):80-9
11919546