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.

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: 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
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 32 Issue 2 Pg. 299-307 (Feb 2012) ISSN: 1524-4636 [Electronic] United States
• PMID: 22095982 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ABCG1 protein, mouse
• ATP Binding Cassette Transporter 1
• ATP Binding Cassette Transporter, Subfamily G, Member 1
• ATP-Binding Cassette Transporters
• Antimicrobial Cationic Peptides
• Apolipoproteins E
• Bone Morphogenetic Proteins
• Hamp protein, mouse
• Hepcidins
• LDN 193189
• Lipoproteins
• Pyrazoles
• Pyrimidines
• Cholesterol
• Iron

Topics

• ATP Binding Cassette Transporter 1
• ATP Binding Cassette Transporter, Subfamily G, Member 1
• ATP-Binding Cassette Transporters (metabolism)
• Animals
• Antimicrobial Cationic Peptides (antagonists & inhibitors)
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (metabolism, physiopathology, prevention & control)
• Bone Morphogenetic Proteins (antagonists & inhibitors, drug effects)
• Cell Differentiation (drug effects)
• Cholesterol (metabolism)
• Disease Models, Animal
• Foam Cells (pathology)
• Hepcidins
• Iron (metabolism)
• Lipoproteins (metabolism)
• Macrophages (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Signal Transduction (drug effects)