| First Author | Lian G | Year | 2019 |
| Journal | EBioMedicine | Volume | 49 |
| Pages | 291-304 | PubMed ID | 31640947 |
| Mgi Jnum | J:291057 | Mgi Id | MGI:6436100 |
| Doi | 10.1016/j.ebiom.2019.09.041 | Citation | Lian G, et al. (2019) Macrophage metabolic reprogramming aggravates aortic dissection through the HIF1alpha-ADAM17 pathway(). EBioMedicine 49:291-304 |
| abstractText | 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-1alpha) in aortic dissection was uncovered. METHODS: Immunochemistry, immunofluorescence, western blot and qPCR were performed to test the change of macrophage HIF-1alpha 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-1alpha activation in the development of aortic dissection in human and mouse models. Mechanistic studies revealed that macrophage HIF-1alpha 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-1alpha. A HIF-1alpha specific inhibitor acriflavine elicited protective effects on aortic dissection dependent on macrophage HIF-1alpha. INTERPRETATION: This study reveals that macrophage metabolic reprogramming activates HIF-1alpha and subsequently promotes aortic dissection progression, suggesting that macrophage HIF-1alpha inhibition might be a potential therapeutic target for treating aortic dissection. |
