Iron accumulation in macrophages promotes the formation of foam cells and development of atherosclerosis
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Cell & Bioscience Open Access
RESEARCH
Iron accumulation in macrophages promotes the formation of foam cells and development of atherosclerosis Jing Cai1†, Meng Zhang2†, Yutong Liu3†, Huihui Li3, Longcheng Shang2, Tianze Xu1, Zhipeng Chen1, Fudi Wang4, Tong Qiao1* and Kuanyu Li3*
Abstract Background: Macrophages that accumulate in atherosclerotic plaques contribute to progression of the lesions to more advanced and complex plaques. Although iron deposition was found in human atherosclerotic plaques, clinical and pre-clinical studies showed controversial results. Several epidemiological studies did not show the positive correlation between a systemic iron status and an incidence of cardiovascular diseases, suggesting that the iron involvement occurs locally, rather than systemically. Results: To determine the direct in vivo effect of iron accumulation in macrophages on the progression of atherosclerosis, we generated Apoe−/− mice with a macrophage-specific ferroportin (Fpn1) deficiency (Apoe−/−Fpn1LysM/ LysM ). Fpn1 deficiency in macrophages dramatically accelerated the progression of atherosclerosis in mice. Pathophysiological evidence showed elevated levels of reactive oxygen species, aggravated systemic inflammation, and altered plaque-lipid composition. Moreover, Fpn1 deficiency in macrophages significantly inhibited the expression of ABC transporters (ABCA1 and ABCG1) by decreasing the expression of the transcription factor LXRα, which reduced cholesterol efflux and therefore promoted foam cell formation and enhanced plaque formation. Iron chelation relieved the symptoms moderately in vivo, but drastically ex vivo. Conclusions: Macrophage iron content in plaques is a critical factor in progression of atherosclerosis. The interaction of iron and lipid metabolism takes place in macrophage-rich atherosclerotic plaques. And we also suggest that altering intracellular iron levels in macrophages by systemic iron chelation or dietary iron restriction may be a potential supplementary strategy to limit or even regress the progression of atherosclerosis. Keywords: Atherosclerosis, Iron metabolism, Fpn1, Macrophages, Foam cell formation
*Correspondence: [email protected]; [email protected] † Jing Cai, Meng Zhang, and Yutong Liu contributed equally to this work 1 Department of Vascular Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, People’s Republic of China 3 Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, People’s Republic of China Full list of author information is available at the end of the article
Background Atherosclerosis is the underlying cause of a majority of clinical cardiovascular events, including myocardial infarction, peripheral artery disease, stroke and coronary artery disease (CAD) [1]. Excessive fatty deposits and inflammatory cells accumulate during the formation and development of atherosclerotic lesions. As the major immune cells in atherosclerotic lesions, macrophages play a critical r
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