| First Author | Kim GD | Year | 2021 |
| Journal | Am J Pathol | Volume | 191 |
| Issue | 6 | Pages | 1118-1134 |
| PubMed ID | 33753024 | Mgi Jnum | J:312306 |
| Mgi Id | MGI:6729798 | Doi | 10.1016/j.ajpath.2021.03.008 |
| Citation | Kim GD, et al. (2021) Macrophage-Hypoxia-Inducible Factor-1alpha Signaling in Carotid Artery Stenosis. Am J Pathol 191(6):1118-1134 |
| abstractText | Macrophages play crucial and diverse roles in the pathogenesis of inflammatory vascular diseases. Macrophages are the principal innate immune cells recruited to arterial walls to govern vascular homeostasis by modulating the proliferation of vascular smooth muscle cells, the reorganization of extracellular matrix components, the elimination of dead cells, and the restoration of normal blood flow. However, chronic sterile inflammation within the arterial walls draws inflammatory macrophages into intimal/neointimal regions that may contribute to disease pathogenesis. In this context, the accumulation and aberrant activation of macrophages in the neointimal regions govern the progression of inflammatory arterial wall diseases. Herein, we report that myeloid-hypoxia-inducible factor-1alpha (HIF1alpha) deficiency attenuates vascular smooth muscle cells and macrophage abundance in stenotic arteries and abrogates carotid neointima formation in vivo. The integrated transcriptomics, Gene Set Enrichment Analysis, metabolomics, and target gene evaluation showed that HIF1alpha represses oxidative phosphorylation, tricarboxylic acid cycle, fatty acid metabolism, and c-MYC signaling pathways while promoting inflammatory, glycolytic, hypoxia response gene expression in stenotic artery macrophages. At the molecular level, proinflammatory agents utilized STAT3 signaling pathways to elevate HIF1alpha expression in macrophages. Collectively, this study uncovers that macrophage-HIF1alpha deficiency restrains the pathogenesis of carotid artery stenosis by rewiring inflammatory and metabolic signaling pathways in macrophages. |
