Experimental Biology and Medicine 232:1014-1020 (2007)
doi: 10.3181/0703-MR-54
(c) 2007 Society for Experimental Biology and Medicine
--------------------------------------------------------------------------------
MINIREVIEW
Macrophage Iron, Hepcidin, and Atherosclerotic Plaque Stability
Jerome l. Sullivan1,2
Department of Pathology, Immunology, and Laboratory Medicine,
University of Florida, College of Medicine, Gainesville, Florida
32610

To whom requests for reprints should be addressed at 1 4475 Old Bear
Run, Winter Park, FL 32792. E-mail: jlsullivan3@gmail.com

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.

Key Words: atherosclerosis * hemochromatosis * hepcidin * iron *
macrophage

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