title: Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis.
abstract: OBJECTIVE
  We recently reported that lowering of macrophage free intracellular iron increases expression of cholesterol efflux transporters ABCA1 and ABCG1 by reducing generation of reactive oxygen species. In this study, we explored whether reducing macrophage intracellular iron levels via pharmacological suppression of hepcidin can increase macrophage-specific expression of cholesterol efflux transporters and reduce atherosclerosis.
  
  
  RESULTS
  To suppress hepcidin, increase expression of the iron exporter ferroportin, and reduce macrophage intracellular iron, we used a small molecule inhibitor of bone morphogenetic protein (BMP) signaling, LDN 193189 (LDN). LDN (10 mg/kg IP b.i.d.) was administered to mice, and its effects on atherosclerosis, intracellular iron, oxidative stress, lipid efflux, and foam cell formation were measured in plaques and peritoneal macrophages. Long-term LDN administration to apolipoprotein E-/- mice increased ABCA1 immunoreactivity within intraplaque macrophages by 3.7-fold (n=8; P=0.03), reduced Oil Red O-positive lipid area by 50% (n=8; P=0.02), and decreased total plaque area by 43% (n=8; P=0.001). LDN suppressed liver hepcidin transcription and increased macrophage ferroportin, lowering intracellular iron and hydrogen peroxide production. LDN treatment increased macrophage ABCA1 and ABCG1 expression, significantly raised cholesterol efflux to ApoA-1, and decreased foam cell formation. All preceding LDN-induced effects on cholesterol efflux were reversed by exogenous hepcidin administration, suggesting modulation of intracellular iron levels within macrophages as the mechanism by which LDN triggers these effects.
  
  
  CONCLUSIONS
  These data suggest that pharmacological manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis.
authors.affiliation: Emory University Hospital Midtown, 550 Peachtree St NE, Atlanta, GA 30308, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Saeed
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Otsuka
authors.forename: Rohini
authors.initials: R
authors.lastname: Polavarapu
authors.forename: Vinit
authors.initials: V
authors.lastname: Karmali
authors.forename: Daiana
authors.initials: D
authors.lastname: Weiss
authors.forename: Talina
authors.initials: T
authors.lastname: Davis
authors.forename: Brad
authors.initials: B
authors.lastname: Rostad
authors.forename: Kimberly
authors.initials: K
authors.lastname: Pachura
authors.forename: Lila
authors.initials: L
authors.lastname: Adams
authors.forename: John
authors.initials: J
authors.lastname: Elliott
authors.forename: W Robert
authors.initials: WR
authors.lastname: Taylor
authors.forename: Jagat
authors.initials: J
authors.lastname: Narula
authors.forename: Frank
authors.initials: F
authors.lastname: Kolodgie
authors.forename: Renu
authors.initials: R
authors.lastname: Virmani
authors.forename: Charles C
authors.initials: CC
authors.lastname: Hong
authors.forename: Aloke V
authors.initials: AV
authors.lastname: Finn
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D005487:Foam Cells / Q000473:pathology*; D064451:Hepcidins; D007501:Iron / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D023181:Antimicrobial Cationic Peptides; D001057:Apolipoproteins E; D019485:Bone Morphogenetic Proteins; C579599:Hamp protein, mouse; D064451:Hepcidins; C554430:LDN 193189; D008074:Lipoproteins; D011720:Pyrazoles; D011743:Pyrimidines; D002784:Cholesterol; D007501:Iron
references.citation: J Immunol. 2008 Aug 15;181(4):2723-31
references.pmid: 18684963
references.citation: Nat Chem Biol. 2008 Jan;4(1):33-41
references.pmid: 18026094
references.citation: J Am Coll Cardiol. 2008 Jun 10;51(23):2199-211
references.pmid: 18534265
references.citation: Circ Res. 2009 Nov 6;105(10):1003-12
references.pmid: 19797172
references.citation: Int J Biochem Cell Biol. 2010 Nov;42(11):1802-7
references.pmid: 20691279
references.citation: J Cell Biochem. 2008 May 15;104(2):629-41
references.pmid: 18189270
references.citation: J Clin Invest. 2007 Aug;117(8):2216-24
references.pmid: 17657311
references.citation: Circulation. 2001 Jan 23;103(3):448-54
references.pmid: 11157699
references.citation: Nat Med. 2008 Dec;14(12):1363-9
references.pmid: 19029982
references.citation: Arterioscler Thromb Vasc Biol. 2006 Apr;26(4):929-34
references.pmid: 16456089
references.citation: Bioorg Med Chem Lett. 2008 Aug 1;18(15):4388-92
references.pmid: 18621530
references.citation: Circ Res. 2010 Aug 20;107(4):485-94
references.pmid: 20576934
references.citation: Circulation. 2002 Jun 25;105(25):2974-80
references.pmid: 12081990
references.citation: Nat Genet. 2006 Dec;38(12):1424-9
references.pmid: 17099713
references.citation: Blood. 2005 Sep 15;106(6):2196-9
references.pmid: 15933050
references.citation: J Am Coll Cardiol. 2012 Jan 10;59(2):166-77
references.pmid: 22154776
references.citation: N Engl J Med. 1999 Jan 14;340(2):115-26
references.pmid: 9887164
references.citation: Circ Res. 2005 Sep 30;97(7):682-9
references.pmid: 16141411
references.citation: ACS Chem Biol. 2010 Feb 19;5(2):245-53
references.pmid: 20020776
references.citation: Arterioscler Thromb Vasc Biol. 2009 Nov;29(11):1930-6
references.pmid: 19729607
references.citation: J Clin Invest. 2007 Dec;117(12):3900-8
references.pmid: 17992262
references.citation: J Surg Res. 2008 Mar;145(1):142-9
references.pmid: 17706674
references.citation: Expert Opin Pharmacother. 2009 Jul;10(10):1587-603
references.pmid: 19527187
references.citation: N Engl J Med. 2005 Apr 21;352(16):1685-95
references.pmid: 15843671
references.citation: J Clin Invest. 2011 Jul;121(7):2921-31
references.pmid: 21646721
references.citation: N Engl J Med. 2007 Sep 27;357(13):1301-10
references.pmid: 17898099
references.citation: Science. 2004 Dec 17;306(5704):2090-3
references.pmid: 15514116
references.citation: Arterioscler Thromb Vasc Biol. 2008 Feb;28(2):258-64
references.pmid: 18006857