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http://purl.uniprot.org/citations/32611235http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/32611235http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/32611235http://purl.org/dc/terms/identifier"doi:10.1161/circresaha.119.315528"xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/author"Han Y."xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/author"Jiang L."xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/author"Carling D."xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/author"Wong E."xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/author"Haskard D.O."xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/author"Mason J.C."xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/author"Boyle J.J."xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/author"Cave L."xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/author"Seneviratne A."xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/author"Long N.J."xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/author"Walter E.R.H."xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/date"2020"xsd:gYear
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/name"Circ Res"xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/pages"928-944"xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/title"Hematoma Resolution In Vivo Is Directed by Activating Transcription Factor 1."xsd:string
http://purl.uniprot.org/citations/32611235http://purl.uniprot.org/core/volume"127"xsd:string
http://purl.uniprot.org/citations/32611235http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/32611235
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