Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis

Omar Saeed, Fumiyuki Otsuka, Rohini Polavarapu, Vinit Karmali, Daiana Weiss, Talina Davis, Brad Rostad, Kimberly Pachura, Lila Adams, John Elliott, W. Robert Taylor, Jagat Narula, Frank Kolodgie, Renu Virmani, Charles C. Hong, Aloke V. Finn

Research output: Contribution to journalArticle

96 Citations (Scopus)

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. Methods and 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. Conclusion-: These data suggest that pharmacological manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis.

Original languageEnglish (US)
Pages (from-to)299-307
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume32
Issue number2
DOIs
StatePublished - Feb 2012
Externally publishedYes

Fingerprint

Hepcidins
Foam Cells
Atherosclerosis
Macrophages
Cholesterol
Pharmacology
Iron
Lipids
Bone Morphogenetic Proteins
Apolipoprotein A-I
Peritoneal Macrophages
Apolipoproteins E
Hydrogen Peroxide
Reactive Oxygen Species
Oxidative Stress
Homeostasis

Keywords

  • ABC transporter
  • hemoglobin
  • macrophages
  • pharmacology
  • reactive oxygen species

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis. / Saeed, Omar; Otsuka, Fumiyuki; Polavarapu, Rohini; Karmali, Vinit; Weiss, Daiana; Davis, Talina; Rostad, Brad; Pachura, Kimberly; Adams, Lila; Elliott, John; Taylor, W. Robert; Narula, Jagat; Kolodgie, Frank; Virmani, Renu; Hong, Charles C.; Finn, Aloke V.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 32, No. 2, 02.2012, p. 299-307.

Research output: Contribution to journalArticle

Saeed, O, Otsuka, F, Polavarapu, R, Karmali, V, Weiss, D, Davis, T, Rostad, B, Pachura, K, Adams, L, Elliott, J, Taylor, WR, Narula, J, Kolodgie, F, Virmani, R, Hong, CC & Finn, AV 2012, 'Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 2, pp. 299-307. https://doi.org/10.1161/ATVBAHA.111.240101
Saeed, Omar ; Otsuka, Fumiyuki ; Polavarapu, Rohini ; Karmali, Vinit ; Weiss, Daiana ; Davis, Talina ; Rostad, Brad ; Pachura, Kimberly ; Adams, Lila ; Elliott, John ; Taylor, W. Robert ; Narula, Jagat ; Kolodgie, Frank ; Virmani, Renu ; Hong, Charles C. ; Finn, Aloke V. / Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2012 ; Vol. 32, No. 2. pp. 299-307.
@article{06f476619a2c49e089d6888c94c6e1a3,
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. Methods and 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. Conclusion-: These data suggest that pharmacological manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis.",
keywords = "ABC transporter, hemoglobin, macrophages, pharmacology, reactive oxygen species",
author = "Omar Saeed and Fumiyuki Otsuka and Rohini Polavarapu and Vinit Karmali and Daiana Weiss and Talina Davis and Brad Rostad and Kimberly Pachura and Lila Adams and John Elliott and Taylor, {W. Robert} and Jagat Narula and Frank Kolodgie and Renu Virmani and Hong, {Charles C.} and Finn, {Aloke V.}",
year = "2012",
month = "2",
doi = "10.1161/ATVBAHA.111.240101",
language = "English (US)",
volume = "32",
pages = "299--307",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "2",

}

TY - JOUR

T1 - Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis

AU - Saeed, Omar

AU - Otsuka, Fumiyuki

AU - Polavarapu, Rohini

AU - Karmali, Vinit

AU - Weiss, Daiana

AU - Davis, Talina

AU - Rostad, Brad

AU - Pachura, Kimberly

AU - Adams, Lila

AU - Elliott, John

AU - Taylor, W. Robert

AU - Narula, Jagat

AU - Kolodgie, Frank

AU - Virmani, Renu

AU - Hong, Charles C.

AU - Finn, Aloke V.

PY - 2012/2

Y1 - 2012/2

N2 - 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. Methods and 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. Conclusion-: These data suggest that pharmacological manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis.

AB - 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. Methods and 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. Conclusion-: These data suggest that pharmacological manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis.

KW - ABC transporter

KW - hemoglobin

KW - macrophages

KW - pharmacology

KW - reactive oxygen species

UR - http://www.scopus.com/inward/record.url?scp=84856225143&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856225143&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.111.240101

DO - 10.1161/ATVBAHA.111.240101

M3 - Article

C2 - 22095982

AN - SCOPUS:84856225143

VL - 32

SP - 299

EP - 307

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 2

ER -