| First Author | Seneviratne A | Year | 2020 |
| Journal | Circ Res | Volume | 127 |
| Issue | 7 | Pages | 928-944 |
| PubMed ID | 32611235 | Mgi Jnum | J:299141 |
| Mgi Id | MGI:6489622 | Doi | 10.1161/CIRCRESAHA.119.315528 |
| Citation | Seneviratne A, et al. (2020) Hematoma Resolution In Vivo Is Directed by Activating Transcription Factor 1. Circ Res 127(7):928-944 |
| abstractText | RATIONALE: The efficient resolution of tissue hemorrhage is an important homeostatic function. In human macrophages in vitro, heme activates an AMPK (AMP-activated protein kinase)/ATF1 (activating transcription factor-1) pathway that directs Mhem macrophages through coregulation of HO-1 (heme oxygenase-1; HMOX1) and lipid homeostasis genes. OBJECTIVE: We asked whether this pathway had an in vivo role in mice. METHODS AND RESULTS: Perifemoral hematomas were used as a model of hematoma resolution. In mouse bone marrow-derived macrophages, heme induced HO-1, lipid regulatory genes including LXR (lipid X receptor), the growth factor IGF1 (insulin-like growth factor-1), and the splenic red pulp macrophage gene Spic. This response was lost in bone marrow-derived macrophages from mice deficient in AMPK (Prkab1(-/)(-)) or ATF1 (Atf1(-/-)). In vivo, femoral hematomas resolved completely between days 8 and 9 in littermate control mice (n=12), but were still present at day 9 in mice deficient in either AMPK (Prkab1(-/-)) or ATF1 (Atf1(-/-); n=6 each). Residual hematomas were accompanied by increased macrophage infiltration, inflammatory activation and oxidative stress. We also found that fluorescent lipids and a fluorescent iron-analog were trafficked to lipid-laden and iron-laden macrophages respectively. Moreover erythrocyte iron and lipid abnormally colocalized in the same macrophages in Atf1(-/-) mice. Therefore, iron-lipid separation was Atf1-dependent. CONCLUSIONS: Taken together, these data demonstrate that both AMPK and ATF1 are required for normal hematoma resolution. Graphic Abstract: An online graphic abstract is available for this article. |
