1. Hematoma Resolution In Vivo Is Directed by Activating Transcription Factor 1
- Author
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Lijun Jiang, Yumeng Han, L. Cave, Joseph J. Boyle, Edward R. H. Walter, Dorian O. Haskard, David Carling, A. Seneviratne, Nicholas J. Long, Justin C. Mason, and Eunice Wong
- Subjects
Male ,Erythrocytes ,Time Factors ,Physiology ,Iron ,Inflammation ,AMP-Activated Protein Kinases ,lipids ,chemistry.chemical_compound ,In vivo ,medicine ,oxidative stress ,Animals ,Insulin-Like Growth Factor I ,Protein kinase A ,Heme ,Cells, Cultured ,Original Research ,Liver X Receptors ,Activating Transcription Factor 1 ,Mice, Knockout ,Hematoma ,ATF1 ,Macrophages ,Membrane Proteins ,AMPK ,Lipid Metabolism ,In vitro ,Cell biology ,DNA-Binding Proteins ,Mice, Inbred C57BL ,Disease Models, Animal ,chemistry ,inflammation ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Female ,hemorrhage ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Heme Oxygenase-1 ,Homeostasis - Abstract
Supplemental Digital Content is available in the text., 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.
- Published
- 2020
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