Abstract 14303: Pharmacologic suppression of Hepcidin by Inhibition of Bone Morphogenetic Protein Signaling Reduces Foam Cell Formation and Atherosclerosis
Introduction: Atherosclerosis is a major etiology of cardiovascular disease. The atheroma is comprised of macrophages that ingest lipids to transform into foam cells. Foam cell formation is reduced by lipid efflux transporters and their athero-protective significance is well established. Earlier findings show that the expression of lipid efflux transporters, ABCA1 and ABCG1, in macrophages is inversely related to oxidative stress, which in turn is closely tied to intracellular free iron. Macrophages lose intracellular free iron through Ferroportin (FPN), which is systemically degraded by a hepatic hormone produced through Bone Morphogenetic Protein (BMP) signaling, called hepcidin. Hypothesis: Selective reduction of intracellular free iron and iron induced oxidative stress within macrophages by suppressing hepcidin through inhibiting BMP signaling may lead to increased lipid efflux, thereby reducing foam cell formation and atherosclerosis.
Methods: To suppress hepcidin and maintain FPN, we used a small molecular inhibitor of BMP signaling, LDN 193189 (LDN). LDN (10 mg/kg ip bid) was administered to mice and its effects on intracellular iron, oxidative stress, ABCA1 and ABCG1 expression, lipid efflux, foam cell formation and atherosclerosis were measured in peritoneal macrophages and plaques at the sinotubular junction.
Results: LDN suppressed hepcidin and maintained FPN to lower intracellular free iron and hydrogen peroxide production. LDN treatment increased ABCA1 and ABCG1 expression, raised lipid efflux by 40% (n=6; p=0.01) and decreased foam cell formation. To ensure specificity, all preceding LDN induced non-foam cell forming effects were reversed by exogenous hepcidin. Long-term LDN administration 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 intraplaque area by 43% (n=8; p=0.001) to limit progression of atherosclerotic lesions.
Conclusion: Suppressing hepcidin by inhibiting BMP signaling with LDN to reduce iron and iron induced oxidative stress within macrophages may be a therapeutic strategy to increase lipid efflux, decrease foam cell formation and limit atherosclerosis.
- © 2011 by American Heart Association, Inc.