Hepcidin Deficiency Protects Against Atherosclerosis

Abstract

Objective— Inflammatory stimuli enhance the progression of atherosclerotic disease. Inflammation also increases the expression of hepcidin, a hormonal regulator of iron homeostasis, which decreases intestinal iron absorption, reduces serum iron levels and traps iron within macrophages. The role of macrophage iron in the development of atherosclerosis remains incompletely understood. The objective of this study was to investigate the effects of hepcidin deficiency and decreased macrophage iron on the development of atherosclerosis. Approach and Results— Hepcidin- and LDL (low-density lipoprotein) receptor-deficient ( Hamp −/− / Ldlr −/− ) mice and Hamp +/+ / Ldlr −/− control mice were fed a high-fat diet for 21 weeks. Compared with control mice, Hamp −/− / Ldlr −/− mice had decreased aortic macrophage activity and atherosclerosis. Because hepcidin deficiency is associated with both increased serum iron and decreased macrophage iron, the possibility that increased serum iron was responsible for decreased atherosclerosis in Hamp −/− / Ldlr −/− mice was considered. Hamp +/+ / Ldlr −/− mice were treated with iron dextran so as to produce a 2-fold increase in serum iron. Increased serum iron did not decrease atherosclerosis in Hamp +/+ / Ldlr −/− mice. Aortic macrophages from Hamp −/− / Ldlr −/− mice had less labile free iron and exhibited a reduced proinflammatory (M1) phenotype compared with macrophages from Hamp +/+ / Ldlr −/− mice. THP1 human macrophages treated with an iron chelator were used to model hepcidin deficiency in vitro. Treatment with an iron chelator reduced LPS (lipopolysaccharide)-induced M1 phenotypic expression and decreased uptake of oxidized LDL. Conclusions— In summary, in a hyperlipidemic mouse model, hepcidin deficiency was associated with decreased macrophage iron, a reduced aortic macrophage inflammatory phenotype and protection from atherosclerosis. The results indicate that decreasing hepcidin activity, with the resulting decrease in macrophage iron, may prove to be a novel strategy for the treatment of atherosclerosis.

New insights into the role of iron in inflammation and atherosclerosis

“…Conversely, in another study deletion of the hepcidin gene ( hamp ) was associated with reduced atherosclerosis in hamp −/− /Ldlr −/− mice along with reduced pro-inflammatory markers in macrophages [73]. In addition, fasting serum LDL was decreased, which might in part be attributable to a genetic overlap in iron and lipid loci [47].…”

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype

“…wild-type, Mgp −/− Hdac9 +/+ , Mgp −/− Hdac9 +/− , and Mgp −/− Hdac9 −/− mice were injected via the tail vein with OsteoSense-680 (PerkinElmer, 5 μl/g each) 24 hours before euthanasia, as described previously 50,51 . Aortas were isolated and analyzed ex vivo by fluorescence reflectance imaging using an Odyssey Imaging System (LI-COR Biotechnology, Lincoln, NE) and software version 3.0.16 52,53 .…”

Organ-organ communication: The liver's perspective

“…In addition to the characterized linking function of adropin 19 and fetuin 33 , a recent study reported that alpha-1-microglobulin (AMBP) exacerbated inflammation and disturbed hepatic fibrotic repair after myocardial infarction through activating Akt, NF-κB, and ERK signaling and promoting macrophage migration and polarization 115 . Another hepatokine, hepcidin, has been proven to regulate macrophage inflammation and arterial stiffness, thus promoting the development of atherosclerosis 116 , 117 . Upregulated fetuin B aggravates myocardial ischemia/reperfusion injury through inhibiting insulin signaling in diabetic mice 118 .…”