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ORIGINAL RESEARCH ARTICLE

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

Wei Li^*,1, Li-Hua Xu^,1,2, Claes Forssell, Jerome L. Sullivan and Xi-Ming Yuan^,3

^* Division of Pharmacology; Division of Experimental Pathology, Department of Clinical and Experimental Medicine; Division of Vascular Surgery, Department of Medicine and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, SE-58185 Sweden; and Burnett College of Biomedical Sciences, University of Central Florida, Orlando, Florida 32816

To whom requests for reprints should be addressed at ³ Division of Experimental Pathology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. E-mail: yuan.ximing{at}inr.liu.se; yuanximing{at}gmail.com

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.

Key Words: atherosclerosis • apoptosis • iron metabolism • lysosomes • macrophages • plaque rupture