Hepcidin Deficiency Protects Against Atherosclerosis

Area of Science:

• Cardiovascular Research
• Iron Metabolism
• Immunology

Background:

• Inflammatory stimuli accelerate atherosclerosis.
• Hepcidin, a regulator of iron homeostasis, increases with inflammation, trapping iron in macrophages.
• The impact of macrophage iron on atherosclerosis is not fully understood.

Purpose of the Study:

• To investigate the effects of hepcidin deficiency and reduced macrophage iron on atherosclerosis development.
• To determine if reduced macrophage iron contributes to atherosclerosis protection in hepcidin-deficient mice.

Main Methods:

• Mice lacking hepcidin and LDL receptors (Hamp-/-/Ldlr-/-) and controls (Hamp+/+/Ldlr-/-) were fed a high-fat diet for 21 weeks.
• Iron dextran was administered to control mice to increase serum iron levels.
• THP1 human macrophages were treated with an iron chelator in vitro to model hepcidin deficiency.

Main Results:

• Hamp-/-/Ldlr-/- mice exhibited reduced aortic macrophage activity and atherosclerosis compared to controls.
• Increased serum iron in control mice did not reduce atherosclerosis.
• Macrophages from hepcidin-deficient mice had less iron and a less proinflammatory (M1) phenotype.
• In vitro, iron chelation reduced M1 phenotype and oxidized LDL uptake in macrophages.

Conclusions:

• Hepcidin deficiency in hyperlipidemic mice led to decreased macrophage iron, reduced inflammation, and protection from atherosclerosis.
• Reducing hepcidin activity and subsequent macrophage iron may be a novel therapeutic approach for atherosclerosis.