Macrophage metabolic reprogramming aggravates aortic dissection through the HIF1α-ADAM17 pathway
Macrophage metabolic reprogramming aggravates aortic dissection through the HIF1α-ADAM17 pathway
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巨噬细胞代谢重编程通过 HIF1 α-ADAM17 通路加重主动脉夹层
DOI：
10.1016/j.ebiom.2019.09.041
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发表时间：
2019-11-01
期刊：
影响因子：
11.1
通讯作者：
Jiang, Changtao
中科院分区：
文献类型：
--
作者：
Lian, Guan;Li, Xiaopeng;Jiang, Changtao
背景：主动脉夹层是一种严重的炎症性血管疾病，死亡率高且治疗选择有限。主动脉夹层的特征包括主动脉炎性细胞浸润和弹性纤维破坏，这突出表明巨噬细胞参与其中。本研究揭示了巨噬细胞缺氧诱导因子1-α（HIF-1α）在主动脉夹层中的作用。
方法：通过免疫组织化学、免疫荧光、蛋白质免疫印迹和定量聚合酶链反应（qPCR）检测两种主动脉夹层模型及人体组织中巨噬细胞HIF-1α的变化。采用代谢组学和海马细胞外流量分析检测参与主动脉夹层发展过程中巨噬细胞的代谢状态。运用染色质免疫沉淀（ChIP）、酶联免疫吸附试验（ELISA）和细胞因子微球检测（CBA）进行机制研究。
结果：在人和小鼠主动脉夹层模型的发展过程中，参与其中的巨噬细胞经历了明显的代谢重编程，尤其是延胡索酸积累，从而诱导HIF-1α激活。机制研究表明，巨噬细胞HIF-1α激活通过增加去整合素和金属蛋白酶结构域17（ADAM17，被确定为HIF-1α的一个新靶基因），引发血管炎症、细胞外基质降解和弹性板断裂。HIF-1α特异性抑制剂吖啶黄对主动脉夹层具有依赖于巨噬细胞HIF-1α的保护作用。
结论：本研究表明，巨噬细胞代谢重编程激活HIF-1α，进而促进主动脉夹层进展，提示抑制巨噬细胞HIF-1α可能是治疗主动脉夹层的一个潜在治疗靶点。（c）2019作者。由爱思唯尔公司出版。
Background: Aortic dissection is a severe inflammatory vascular disease with high mortality and limited therapeutic options. The hallmarks of aortic dissection comprise aortic inflammatory cell infiltration and elastic fiber disruption, highlighting the involvement of macrophage. Here a role for macrophage hypoxia-inducible factor 1-alpha (HIF-1 alpha) in aortic dissection was uncovered.Methods: Immunochemistry, immunofluorescence, western blot and qPCR were performed to test the change of macrophage HIF-1 alpha in two kinds of aortic dissection models and human tissues. Metabolomics and Seahorse extracellular flux analysis were used to detect the metabolic state of macrophages involved in the development of aortic dissection. Chromatin Immunoprecipitation (ChIP), enzyme-linked immunosorbent assay (ELISA) and cytometric bead array (CBA) were employed for mechanistic studies.Findings: Macrophages involved underwent distinct metabolic reprogramming, especially fumarate accumulation, thus inducing HIF-1 alpha activation in the development of aortic dissection in human and mouse models. Mechanistic studies revealed that macrophage HIF-1 alpha activation triggered vascular inflammation, extracellular matrix degradation and elastic plate breakage through increased a disintegrin and metallopeptidase domain 17 (ADAM17), identified as a novel target gene of HIF-1 alpha. A HIF-1 alpha specific inhibitor acriflavine elicited protective effects on aortic dissection dependent on macrophage HIF-1 alpha.Interpretation: This study reveals that macrophage metabolic reprogramming activates HIF-1 alpha and subsequently promotes aortic dissection progression, suggesting that macrophage HIF-1 alpha inhibition might be a potential therapeutic target for treating aortic dissection. (c) 2019 The Authors. Published by Elsevier B.V.