Macrophage iron, hepcidin, and atherosclerotic plaque stability.
Hepcidin has emerged as the key hormone in the regulation of iron balance and recycling. Elevated levels increase iron in macrophages and inhibit gastrointestinal iron uptake. The physiology of hepcidin suggests an additional mechanism by which iron depletion could protect against atherosclerotic lesion progression. Without hepcidin, macrophages retain less iron. Very low hepcidin levels occur in iron deficiency anemia and also in homozygous hemochromatosis. There is defective retention of iron in macrophages in hemochromatosis and also evidently no increase in atherosclerosis in this disorder. In normal subjects with intact hepcidin responses, atherosclerotic plaque has been reported to have roughly an order of magnitude higher iron concentration than that in healthy arterial wall. Hepcidin may promote plaque destabilization by preventing iron mobilization from macrophages within atherosclerotic lesions; the absence of this mobilization may result in increased cellular iron loads, lipid peroxidation, and progression to foam cells. Marked downregulation of hepcidin (e.g., by induction of iron deficiency anemia) could accelerate iron loss from intralesional macrophages. It is proposed that the minimally proatherogenic level of hepcidin is near the low levels associated with iron deficiency anemia or homozygous hemochromatosis. Induced iron deficiency anemia intensely mobilizes macrophage iron throughout the body to support erythropoiesis. Macrophage iron in the interior of atherosclerotic plaques is not exempt from this process. Decreases in both intralesional iron and lesion size by systemic iron reduction have been shown in animal studies. It remains to be confirmed in humans that a period of systemic iron depletion can decrease lesion size and increase lesion stability as demonstrated in animal studies. The proposed effects of hepcidin and iron in plaque progression offer an explanation of the paradox of no increase in atherosclerosis in patients with hemochromatosis despite a key role of iron in atherogenesis in normal subjects.
Sullivan
Jerome L
JL
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, College of Medicine, Gainesville, Florida 32610, USA. jlsullivan3@gmail.com
D018798:Anemia, Iron-Deficiency / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D015536:Down-Regulation; D004920:Erythropoiesis; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D006432:Hemochromatosis / Q000151:congenital / Q000378:metabolism / Q000473:pathology; D064451:Hepcidins; D006801:Humans; D007408:Intestinal Absorption / Q000235:genetics; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D015227:Lipid Peroxidation; D036361:Peptide Hormones / Q000378:metabolism*
D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D036361:Peptide Hormones; D007501:Iron