Aberrant STING activation promotes macrophage senescence by suppressing autophagy in vascular aging from diabetes
Huiqing Ding, Quan Zhang, Rukai Yang, Liyao Fu, Hejun Jiang, Qingyi Zhu, Shi Tai
Abstract
<h2>Summary</h2> Diabetic vascular aging is driven by macrophage senescence, which propagates senescence-associated secretory phenotypes (SASP), exacerbating vascular dysfunction. This study utilized a type 2 diabetes mellitus (T2DM) mouse model induced by streptozotocin injection and a high-fat diet to investigate the role of STING in macrophage senescence. Vascular aging markers and senescent macrophages were assessed <i>in vivo</i>, while <i>in vitro</i>, high glucose treatment induced macrophage senescence, enhancing senescence in co-cultured vascular smooth muscle cells. Mechanistic studies revealed that STING activation inhibits autophagy by phosphorylating ULK1 at S757, accelerating senescence. Pharmacological modulation showed that the STING inhibitor H-151 alleviates, while the agonist DMXAA enhances, senescence. These findings highlight the STING-autophagy axis as a critical driver of macrophage senescence, offering insights into the molecular mechanisms of diabetic vascular aging and identifying potential therapeutic targets to mitigate vascular complications in diabetes.