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ATF3 协调心脏巨噬细胞的存活和增殖，并防止缺血再灌注损伤。

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

机构信息

Beijing Anzhen Hospital of Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China.

Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA, USA.

出版信息

Nat Cardiovasc Res. 2024 Jan;3(1):28-45. doi: 10.1038/s44161-023-00392-x. Epub 2024 Jan 4.

DOI:10.1038/s44161-023-00392-x
PMID:39195894
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11358155/
Abstract

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.

摘要

心脏驻留的 MerTK 巨噬细胞在缺血性损伤后发挥多种保护作用；然而，调节其命运的机制尚未完全阐明。在本研究中，我们表明，GAS6 诱导的转录因子激活转录因子 3（ATF3）通过抑制参与 I 型干扰素表达（Ifih1 和 Ifnb1）和细胞凋亡（Apaf1）的多个基因的转录，防止 MerTK 巨噬细胞在缺血再灌注（IR）损伤后的细胞凋亡。心脏巨噬细胞或髓样细胞中缺乏 ATF3 的小鼠在 IR 后表现出过多的 MerTK 心脏巨噬细胞丢失、血管生成不良和心脏功能恶化，而 MerTK 心脏巨噬细胞的转移可挽救这些变化。GAS6 的给药以依赖于 ATF3 的方式改善心脏修复。最后，我们表明，在缺血性心脏病患者中，GAS6 和 ATF3 的表达与主要不良心脏事件的风险呈负相关。这些结果表明，GAS6-ATF3 轴通过调节 MerTK 心脏巨噬细胞的存活和/或增殖对 IR 损伤具有保护作用。

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