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Monocytes and neutrophils expressing myeloperoxidase occur in fibrous caps and thrombi in unstable coronary plaques

Fabio R Tavora, Mary Ripple, Ling Li and Allen P Burke*

BMC Cardiovascular Disorders 2009, 9:27  doi:10.1186/1471-2261-9-27

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Intraplaque iron as a modifiable atherogenic factor.

Jerome Sullivan   (2009-07-01 13:42)  University of Central Florida College of Medicine email

Comment on: Tavora F, et al. BMC Cardiovascular Disorders 2009; 9(1):27.

The significance of the findings of Tavora et al (1) on iron and myeloperoxidase in unstable atherosclerotic plaques is best appreciated in the context of the growing literature on the role of iron as a modifiable risk factor for atherosclerosis (2). The study also provides evidence compatible with the "iron/heart hypothesis" that postulates a protective effect of iron depletion against cardiovascular disease (3-5).

Significant increases in iron concentration are present in human atherosclerotic lesions and in lesions in cholesterol fed animals in comparison to levels in the healthy arterial wall (6-8). Iron concentration (7) and induction of ferritin expression (9) are increased in very early lesions in cholesterol fed rabbits. Systemic iron reduction can decrease the intraplaque concentration of iron (10). In recent animal studies, depletion of lesion iron levels in vivo by phlebotomy, systemic iron chelation treatment or dietary iron restriction reduces lesion size and/or increases plaque stability (10-12).

A study of ex vivo human carotid atherosclerotic lesions found transferrin receptor 1 (TfR1) expression positively correlated with macrophage infiltration, ectopic lysosomal cathepsin L and ferritin expression (13). Highly expressed TfR1 and ferritin in CD68 positive macrophages were significantly associated with development and severity of human carotid plaques. The findings suggest that pathologic macrophage iron metabolism may contribute to vulnerability of human atheroma.

Several factors associated with increased arterial disease or increased cardiovascular events are also associated with increased plaque iron. Infusion of angiotensin II in rats increases ferritin levels and arterial thickness (14). These changes are reversed by treatment with the iron chelator deferoxamine. A human polymorphism for haptoglobin associated with increased cardiovascular disease is characterized by increased lesional iron (15). Heme oxygenase 1 (HO1) is a key component of the system for mobilization of iron from macrophages. Human HO1 promoter polymorphisms associated with weaker upregulation of the enzyme are associated with increased cardiovascular disease (16;17). The hormone hepcidin promotes retention of iron within macrophages and is upregulated by inflammation-induced synthesis of IL-6. The association of cardiovascular disease with inflammation may be in part caused by elevated hepcidin levels that promote retention of iron within plaque macrophages (2).

Iron depletion has been proposed as a protective factor against cardiovascular disease. Increasing evidence suggests that an important mechanism for this protection involves a reduction in iron levels within atherosclerotic plaque. Diminished hepcidin levels and defective retention of iron within arterial macrophages in genetic hemochromatosis may explain why there is little evidence of increased atherosclerosis in this disorder despite systemic iron overload (18). Protection against atherosclerotic lesions in hemochromatosis has been reported (19).

Tavora et al (1) suggest that the molecular relationship between iron and myeloperoxidase is unknown although they recognize that myeloperoxidase contains iron. It appears possible that myeloperoxidase activity is decreased in iron deficiency (20-22). Iron could be a limiting factor for myeloperoxidase formation at very low iron levels. Diminished inflammatory injury in association with reduction in myeloperoxidase activity by induced iron deficiency was first reported 20 years ago (20). Myeloperoxidase is thus a potentially modifiable coronary risk factor. Future studies are needed to determine if induced depletion of plaque iron can also lower intraplaque myeloperoxidase levels.

Jerome L. Sullivan, MD, PhD
University of Central Florida College of Medicine
jlsullivan3@gmail.com


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