Overexpression of Transferrin Receptor and Ferritin Related to Clinical Symptoms and Destabilization of Human Carotid Plaques

Abstract

Accumulation of tissue iron has been implicated in development of atherosclerotic lesions mainly because of increased iron-catalyzed oxidative injury. However, it remains unknown whether cellular iron import and storage in human atheroma are related to human atheroma development. We found that transferrin receptor 1 (TfR1), a major iron importer, is highly expressed in foamy macrophages and some smooth muscle cells in intimal lesions of human carotid atheroma, mainly in cytoplasmic accumulation patterns. In 52 human carotid atherosclerotic lesions, TfR1 expression was positively correlated with macrophage infiltration, ectopic lysosomal cathepsin L, and ferritin expression. Highly expressed TfR1 and ferritin in CD68-positive macrophages were significantly associated with development and severity of human carotid plaques, smoking, and patient's symptoms. The findings suggest that pathologic macrophage iron metabolism may contribute to vulnerability of human atheroma, established risk factors, and their clinical symptoms. The cytoplasmic overexpression of TfR1 may be the result of lysosomal dysfunction and ectopic accumulation of lysosomal cathepsin L caused by atheroma-relevant lipids in atherogenesis.

Hepcidin Destabilizes Atherosclerotic Plaque Via Overactivating Macrophages After Erythrophagocytosis

“…14 A recent study found that pathological iron metabolism in macrophages contributes to vulnerability of human carotid plaque. 21 However, the critical regulator of the phenotypic switching of the iron loaded macrophages remains to be verified. In this context, our results demonstrated that there is the endogenous expression in the atherosclerotic plaque and hepcidin is a critical mediator of plaque destabilization and ox-LDL-exaggerated lipids accumulation, oxidative stress, inflammation, and apoptosis in macrophages after erythrophagocytosis, thus providing a novel insight into the understanding of "iron hypothesis" in the pathogenesis of atherosclerosis.…”

Liver X Receptor Activation Stimulates Iron Export in Human Alternative Macrophages

“…By contrast, iron bound to ferritin or transferrin is less reactive. 27,28 Previously, we reported the presence of a CD68 + MR + macrophage subpopulation in human atherosclerotic plaques, which closely resembles in vitro IL-4-polarized M2 macrophages, which are distinct from the CD68 + MR − subpopulation by morphology, localization, and function. 13,29 Immunohistological analysis showed that CD68 + MR + macrophages colocalize with iron deposits, whereas CD68 + MR − macrophages are poor in iron, suggesting functional differences in terms of iron handling.…”

Biomimetic Materials Synthesis from Ferritin-Related, Cage-Shaped Proteins

“…Indeed, Douglas and co-workers have been able to synthesize magnetite NPs encapsulated within the internal cavity of recombinant HuHFt, which possessed T2* MRI properties comparing favourably with known iron oxide MRI contrast agents (e.g., USPIO; Uchida et al, 2008). The same group has hypothesized that ferritins, which often accumulate in human plaques, may serve as an intrinsic vehicle for targeting plaque macrophages (Li et al, 2008), and has demonstrated that modified ferritin cages can be used as fluorescence or MRI agents for in vivo detection of vascular macrophages (Terashima et al, 2011).…”