Macrophage metabolic reprogramming ameliorates diabetes-induced microvascular dysfunction
Qiuyang Zhang, Huiying Zhang, Si-Guo Feng, Mu-Di Yao, Jing-juan Ding, Xiu‐Miao Li, Rong Ye, Qing Liu, Jin Yao, Biao Yan
Abstract
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. • A significant up-regulation of cSPECC1 expression in diabetic retinas and in macrophages responding to diabetic stress. • CSPECC1 knockdown in macrophages attenuates M1 macrophage polarization and disrupts macrophage-endothelial crosstalk. • CSPECC1 knockdown attenuates macrophage-mediated retinal inflammation and diabetic vascular function. • CSPECC1 orchestrates macrophage metabolic reprogramming by stabilizing GPX2 mRNA. • 12-HETE is a critical mediator in macrophage homeostasis and its interplay with endothelial cells, and Exogenous 12-HETE supplementation interrupts the anti-angiogenic effects of cSPECC1 knockdown.