Elevated Hepcidin Expression in Human Carotid Atheroma: Sex-Specific Differences and Associations with Plaque Vulnerability

Author:

Yuan Xi-Ming1ORCID,Sultana Nargis2,Ghosh-Laskar Moumita3,Li Wei4ORCID

Affiliation:

1. Occupational and Environmental Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, 581 85 Linköping, Sweden

2. Laboratory Medicine, Linköping University Hospital, 581 85 Linköping, Sweden

3. Research & Development, Cytiva, 753 23 Uppsala, Sweden

4. Obstetrics and Gynaecology in Linköping, Department of Biomedical and Clinical Sciences, Linköping University, 581 85 Linköping, Sweden

Abstract

Hepcidin is upregulated by increased body iron stores and inflammatory cytokines. It is associated with cardiovascular events, arterial stiffness, and increased iron accumulation in human atheroma with hemorrhage. However, it is unknown whether the expression of hepcidin in human carotid plaques is related to plaque severity and whether hepcidin expression differs between men and women. Carotid samples from 58 patients (38 males and 20 females) were immunostained with hepcidin, macrophages, ferritin, and transferrin receptor. Immunocytochemistry of hepcidin was performed on THP-1 macrophages exposed to iron or 7betahydroxycholesterol. Hepcidin expression significantly increases with the progression of human atherosclerotic plaques. Plaques of male patients have significantly higher levels of hepcidin. Expressions of hepcidin are significantly correlated with the accumulation of CD68-positive macrophages and transferrin receptor 1 (TfR1) and apoptosis. In vitro, hepcidin is significantly increased in macrophages exposed to iron and moderately increased following 7-oxysterol treatment. In the cultured cells, suppression of hepcidin protected against macrophage cell death, lysosomal membrane permeabilization, and oxidative stress. Hepcidin may play a crucial role in the development and progression of atherosclerosis. The differential expression of hepcidin in male and female patients and its significant correlations with plaque severity, highlight the potential of hepcidin as a biomarker for risk stratification and therapeutic targeting in atherosclerosis.

Funder

Torsten and Ragnar Söderbergs Foundation

Stroke Foundation

Publisher

MDPI AG

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1. Current Concepts in the Pathogenesis of Anemia and Erythrocytosis;Comprehensive Hematology and Stem Cell Research;2024

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