ATF3 coordinates the survival and proliferation of cardiac macrophages and protects against ischemia–reperfusion injury

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2024年1月4日

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Yihui Shao,
Yang Li,
Yan Liu,
Shuolin Zhu,
Jianing Wu,
Ke Ma,
Guoqi Li,
Shan Huang,
Haichu Wen,
Congcong Zhang,
Xin-liang Ma,
Ping Li,
Jie Du,
Yulin Li

摘要

Cardiac resident MerTK⁺ macrophages exert multiple protective roles after ischemic injury; however, the mechanisms regulating their fate are not fully understood. In the present study, we show that the GAS6-inducible transcription factor, activating transcription factor 3 (ATF3), prevents apoptosis of MerTK⁺ macrophages after ischemia–reperfusion (IR) injury by repressing the transcription of multiple genes involved in type I interferon expression (Ifih1 and Ifnb1) and apoptosis (Apaf1). Mice lacking ATF3 in cardiac macrophages or myeloid cells showed excessive loss of MerTK⁺ cardiac macrophages, poor angiogenesis and worse heart dysfunction after IR, which were rescued by the transfer of MerTK⁺ cardiac macrophages. GAS6 administration improved cardiac repair in an ATF3-dependent manner. Finally, we showed a negative association of GAS6 and ATF3 expression with the risk of major adverse cardiac events in patients with ischemic heart disease. These results indicate that the GAS6–ATF3 axis has a protective role against IR injury by regulating MerTK⁺ cardiac macrophage survival and/or proliferation.