Macrophages play an important role in the development of vascular diseases, with their homeostasis closely linked to metabolic reprogramming. This study aims to explore the role of circular RNA-mediated epigenetic remodeling in maintaining macrophage homeostasis during diabetes-induced microvascular dysfunction. We identified a circular RNA, circRNA-sperm antigen with calponin homology and coiled-coil domains 1 (cSPECC1), which is significantly up-regulated in diabetic retinas and in macrophages under diabetic stress. cSPECC1 knockdown in macrophages attenuates M1 macrophage polarization and disrupts macrophage-endothelial crosstalk in vitro. cSPECC1 knockdown in macrophages mitigates diabetes-induced retinal inflammation and ameliorates retinal vascular dysfunction. Mechanistically, cSPECC1 regulates GPX2 expression by recruiting eIF4A3, enhancing GPX2 mRNA stability and altering arachidonic acid metabolism. The metabolic intermediate 12-HETE has emerged as a key mediator, regulating both macrophage homeostasis and the crosstalk between macrophages and endothelial cells. Exogenous 12-HETE supplementation interrupts the anti-angiogenic effects of cSPECC1 knockdown. Collectively, circSPECC1 emerges as a novel regulator of macrophage-mediated vascular integrity and inflammation. Targeting the metabolic reprogramming of macrophages presents a promising therapeutic strategy for mitigating diabetes-induced vascular dysfunction.

中文翻译：

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巨噬细胞代谢重编程可改善糖尿病诱导的微血管功能障碍


巨噬细胞在血管疾病的发展中起着重要作用，它们的稳态与代谢重编程密切相关。本研究旨在探讨环状 RNA 介导的表观遗传重塑在糖尿病诱导的微血管功能障碍期间维持巨噬细胞稳态中的作用。我们鉴定了一种环状 RNA，circRNA-精子抗原，具有钙调蛋白同源性和卷曲螺旋结构域 1 （cSPECC1），它在糖尿病视网膜和糖尿病应激下的巨噬细胞中显着上调。巨噬细胞中的 cSPECC1 敲低可减弱 M1 巨噬细胞极化，并在体外破坏巨噬细胞-内皮细胞串扰。巨噬细胞中的 cSPECC1 敲低可减轻糖尿病诱导的视网膜炎症并改善视网膜血管功能障碍。从机制上讲，cSPECC1 通过募集 eIF4A3 来调节 GPX2 表达，增强 GPX2 mRNA 稳定性并改变花生四烯酸代谢。代谢中间体 12-HETE 已成为一种关键介质，可调节巨噬细胞稳态以及巨噬细胞与内皮细胞之间的串扰。外源性 12-HETE 补充剂会中断 cSPECC1 敲低的抗血管生成作用。总的来说，circSPECC1 作为巨噬细胞介导的血管完整性和炎症的新型调节因子出现。靶向巨噬细胞的代谢重编程为减轻糖尿病诱导的血管功能障碍提供了一种有前途的治疗策略。