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Iron accumulation in macrophages promotes the formation of foam cells and development of atherosclerosis
Cell and Bioscience ( IF 7.5 ) Pub Date : 2020-11-26 , DOI: 10.1186/s13578-020-00500-5 Jing Cai , Meng Zhang , Yutong Liu , Huihui Li , Longcheng Shang , Tianze Xu , Zhipeng Chen , Fudi Wang , Tong Qiao , Kuanyu Li
Cell and Bioscience ( IF 7.5 ) Pub Date : 2020-11-26 , DOI: 10.1186/s13578-020-00500-5 Jing Cai , Meng Zhang , Yutong Liu , Huihui Li , Longcheng Shang , Tianze Xu , Zhipeng Chen , Fudi Wang , Tong Qiao , Kuanyu Li
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. 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. 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.
中文翻译:
铁在巨噬细胞中的积累促进泡沫细胞的形成和动脉粥样硬化的发展
积聚在动脉粥样硬化斑块中的巨噬细胞有助于将病变发展为更晚期和更复杂的斑块。尽管在人的动脉粥样硬化斑块中发现了铁沉积,但临床和临床前研究显示有争议的结果。几项流行病学研究并未显示全身铁质状况与心血管疾病的发病率之间存在正相关关系,这表明铁质参与是局部而非全身性的。为了确定铁在巨噬细胞中积累对动脉粥样硬化进展的直接体内影响,我们产生了具有巨噬细胞特异性铁转运蛋白(Fpn1)缺乏症(Apoe-/-Fpn1LysM / LysM)的Apoe-/-小鼠。巨噬细胞中Fpn1的缺乏显着加速了小鼠动脉粥样硬化的发展。病理生理学证据显示活性氧水平升高,全身炎症加重和斑块脂质组成改变。此外,巨噬细胞中的Fpn1缺乏通过降低转录因子LXRα的表达而显着抑制了ABC转运蛋白(ABCA1和ABCG1)的表达,从而降低了胆固醇外流,从而促进了泡沫细胞的形成和斑块的形成。铁螯合剂可在体内适度缓解症状,但在离体时可大大缓解症状。斑块中的巨噬细胞铁含量是动脉粥样硬化进展的关键因素。铁和脂质代谢的相互作用发生在富含巨噬细胞的动脉粥样硬化斑块中。
更新日期:2020-11-27
中文翻译:
铁在巨噬细胞中的积累促进泡沫细胞的形成和动脉粥样硬化的发展
积聚在动脉粥样硬化斑块中的巨噬细胞有助于将病变发展为更晚期和更复杂的斑块。尽管在人的动脉粥样硬化斑块中发现了铁沉积,但临床和临床前研究显示有争议的结果。几项流行病学研究并未显示全身铁质状况与心血管疾病的发病率之间存在正相关关系,这表明铁质参与是局部而非全身性的。为了确定铁在巨噬细胞中积累对动脉粥样硬化进展的直接体内影响,我们产生了具有巨噬细胞特异性铁转运蛋白(Fpn1)缺乏症(Apoe-/-Fpn1LysM / LysM)的Apoe-/-小鼠。巨噬细胞中Fpn1的缺乏显着加速了小鼠动脉粥样硬化的发展。病理生理学证据显示活性氧水平升高,全身炎症加重和斑块脂质组成改变。此外,巨噬细胞中的Fpn1缺乏通过降低转录因子LXRα的表达而显着抑制了ABC转运蛋白(ABCA1和ABCG1)的表达,从而降低了胆固醇外流,从而促进了泡沫细胞的形成和斑块的形成。铁螯合剂可在体内适度缓解症状,但在离体时可大大缓解症状。斑块中的巨噬细胞铁含量是动脉粥样硬化进展的关键因素。铁和脂质代谢的相互作用发生在富含巨噬细胞的动脉粥样硬化斑块中。