GATA6 regulates macrophage polarization via the CSF1 signaling pathway in acute myocardial infarction.

Macrophage-mediated inflammation plays a crucial role in myocardial infarction (MI) and subsequent cardiac remodeling. However, the transcriptional mechanisms regulating macrophage polarization in the infarcted heart remain incompletely understood. GATA binding protein 6 (GATA6) is a transcription factor involved in macrophage identity, but its role in myocardial infarction has not been fully defined. A murine MI model was established by permanent ligation of the left anterior descending coronary artery. LysM-Cre-mediated myeloid-specific Gata6 deletion was used to evaluate the in vivo function of GATA6. Macrophage responses were assessed using immunofluorescence staining, flow cytometry, Western blotting, quantitative PCR, and ELISA. In vitro experiments were performed in RAW264.7 macrophages exposed to hypoxia. Recombinant CSF1 was used in rescue experiments. GATA6 expression was markedly increased in F4/80-positive macrophages within the infarct border zone after MI. GATA6 deficiency reduced hypoxia-induced Csf1 expression and attenuated ERK phosphorylation. Loss of GATA6 decreased the proportion of CD206-positive macrophages and reduced IL-10 secretion, while additional polarization-associated markers further supported impaired anti-inflammatory-like polarization. Recombinant CSF1 restored ERK activation and macrophage polarization in GATA6-deficient cells. In vivo, myeloid-specific Gata6 deletion increased infarct size, impaired cardiac function, reduced CD206-positive F4/80-positive macrophages, and increased inflammatory cytokine responses after MI. GATA6-associated CSF1/ERK signaling promotes anti-inflammatory-like macrophage polarization and limits myocardial injury after myocardial infarction.