Iron accumulation in macrophages promotes the formation of foam cells and development of atherosclerosis.
Iron accumulation in macrophages promotes the formation of foam cells and development of atherosclerosis.
复制标题
巨噬细胞中铁的积累促进泡沫细胞的形成和动脉粥样硬化的发展
DOI：
10.1186/s13578-020-00500-5
复制
发表时间：
2020-11-26
影响因子：
7.5
通讯作者：
Li K
中科院分区：
文献类型：
--
作者：
Cai J;Zhang M;Liu Y;Li H;Shang L;Xu T;Chen Z;Wang F;Qiao T;Li K
在动脉粥样硬化斑块中积累的巨噬细胞有助于病变进展为更晚期和复杂的斑块。虽然在人类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了有争议的结果。一些流行病学研究没有显示全身铁状态与心血管疾病发病率之间的正相关性，表明铁参与局部发生，而不是全身性。为了确定巨噬细胞中铁积累对动脉粥样硬化进展的直接体内作用，我们产生了巨噬细胞特异性铁转运蛋白（Fpn 1）缺乏的Apoe−/−小鼠（Apoe−/− Fpn 1 LysM/LysM）。巨噬细胞中fpn 1缺陷显著加速了小鼠动脉粥样硬化的进展。病理生理学证据显示活性氧水平升高，全身炎症加剧，斑块脂质组成改变。此外，巨噬细胞中Fpn 1缺陷通过降低转录因子LXRα的表达显著抑制ABC转运蛋白（ABCA 1和ABCG 1）的表达，从而减少胆固醇流出，从而促进泡沫细胞形成并增强斑块形成。铁螯合缓解症状中度体内，但大大离体。斑块中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。我们还认为，通过全身性铁螯合或膳食铁限制来改变巨噬细胞内铁水平可能是限制甚至逆转动脉粥样硬化进展的潜在补充策略。
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.
登录
查看更多内容
影响因子：
20.1
作者：
Tabas I;Bornfeldt KE
通讯作者：
Bornfeldt KE
影响因子：
29
作者：
Donovan, A;Lima, CA;Andrews, NC
通讯作者：
Andrews, NC
影响因子：
5.6
作者：
Hu, Xiaorong;Cai, Xinyong;Du, Xianjin
通讯作者：
Du, Xianjin
DOI：
10.1038/nri3520
发表时间：
2013-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
--
作者：
Sullivan, Jerome L.
通讯作者：
Sullivan, Jerome L.