Hematoma Resolution In Vivo Is Directed by Activating Transcription Factor 1.
Circ Res
; 127(7): 928-944, 2020 09 11.
Article
em En
| MEDLINE
| ID: mdl-32611235
ABSTRACT
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 ANDRESULTS:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fator 1 Ativador da Transcrição
/
Proteínas Quinases Ativadas por AMP
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Hematoma
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Macrófagos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Circ Res
Ano de publicação:
2020
Tipo de documento:
Article