1. Academic Validation
  2. Macrophage metabolic reprogramming aggravates aortic dissection through the HIF1α-ADAM17 pathway✰

Macrophage metabolic reprogramming aggravates aortic dissection through the HIF1α-ADAM17 pathway✰

  • EBioMedicine. 2019 Nov;49:291-304. doi: 10.1016/j.ebiom.2019.09.041.
Guan Lian 1 Xiaopeng Li 1 Linqi Zhang 1 Yangming Zhang 1 Lulu Sun 1 Xiujuan Zhang 1 Huiying Liu 1 Yanli Pang 2 Wei Kong 1 Tao Zhang 3 Xian Wang 4 Changtao Jiang 5
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China.
  • 2 Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China.
  • 3 Department of Vascular Surgery, Peking University People's Hospital, Beijing 100044, China. Electronic address: taozhang@bjmu.edu.cn.
  • 4 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. Electronic address: xwang@bjmu.edu.cn.
  • 5 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. Electronic address: jiangchangtao@bjmu.edu.cn.
Abstract

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-1α) in aortic dissection was uncovered.

Methods: Immunochemistry, immunofluorescence, western blot and qPCR were performed to test the change of macrophage HIF-1α 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-1α activation in the development of aortic dissection in human and mouse models. Mechanistic studies revealed that macrophage HIF-1α 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-1α. A HIF-1α specific inhibitor acriflavine elicited protective effects on aortic dissection dependent on macrophage HIF-1α.

Interpretation: This study reveals that macrophage metabolic reprogramming activates HIF-1α and subsequently promotes aortic dissection progression, suggesting that macrophage HIF-1α inhibition might be a potential therapeutic target for treating aortic dissection.

Keywords

ADAM17; Aortic dissection; HIF-1α; Macrophage.

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