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

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.

• Authors: Guan Lian, Xiaopeng Li, Linqi Zhang, Yangming Zhang, Lulu Sun, Xiujuan Zhang, Huiying Liu, Yanli Pang, Wei Kong, Tao Zhang, Xian Wang, Changtao Jiang
• Journal: EBioMedicine (EBioMedicine) Vol. 49 Pg. 291-304 (Nov 2019) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 31640947 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• HIF1A protein, human
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Angiotensin II
• Aminopropionitrile
• Acriflavine
• ADAM17 Protein

Topics

• ADAM17 Protein (metabolism)
• Acriflavine (pharmacology, therapeutic use)
• Aminopropionitrile
• Aortic Dissection (drug therapy, metabolism, pathology)
• Angiotensin II (pharmacology)
• Animals
• Disease Models, Animal
• Disease Progression
• HEK293 Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Macrophages (drug effects, metabolism)
• Male
• Mice, Inbred C57BL
• Up-Regulation (drug effects)