Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China; Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, 646000, China; Sichuan Clinical Research Center for Nephropathy, Sichuan, 646000, China.
Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, 646000, China; Sichuan Clinical Research Center for Nephropathy, Sichuan, 646000, China.
Biochem Biophys Res Commun. 2023 Aug 6;668:82-89. doi: 10.1016/j.bbrc.2023.05.081. Epub 2023 May 22.
Chronic hyperglycemia-induced impairment of angiogenesis is important in diabetic foot ulcer (DFU). Additionally, the stimulator of interferon gene (STING), which is a key protein in innate immunity, mediates palmitic acid-induced lipotoxicity in metabolic diseases through oxidative stress-induced STING activation. However, the role of STING in DFU is unknown. In this study, we established a DFU mouse model with streptozotocin (STZ) injection and found that the expression of STING was significantly increased in the vascular endothelial cells of wound tissues from diabetic patients and in the STZ-induced diabetic mouse model. We further established high glucose (HG)-induced endothelial dysfunction with rat vascular endothelial cells and found that the expression of STING was also increased by high-glucose treatment. Moreover, the STING inhibitor, C176, promoted diabetic wound healing, whereas the STING activator, DMXAA, inhibited diabetic wound healing. Consistently, STING inhibition reversed the HG-induced reduction of CD31 and vascular endothelial growth factor (VEGF), inhibited apoptosis, and promoted migration of endothelial cells. Notably, DMXAA treatment alone was sufficient to induce endothelial cell dysfunction as a high-glucose treatment. Mechanistically, STING mediated HG-induced vascular endothelial cell dysfunction by activating the interferon regulatory factor 3/nuclear factor kappa B pathway. In conclusion, our study reveals an endothelial STING activation-mediated molecular mechanism in the pathogenesis of DFU and identifies STING as a novel potential therapeutic target for DFU.
慢性高血糖诱导的血管生成损伤在糖尿病足溃疡（DFU）中很重要。此外，干扰素基因刺激物（STING）是先天免疫中的关键蛋白，通过氧化应激诱导的 STING 激活，介导代谢疾病中的棕榈酸诱导的脂毒性。然而，STING 在 DFU 中的作用尚不清楚。在这项研究中，我们通过链脲佐菌素（STZ）注射建立了 DFU 小鼠模型，发现 STING 的表达在糖尿病患者伤口组织的血管内皮细胞和 STZ 诱导的糖尿病小鼠模型中显著增加。我们进一步建立了高糖（HG）诱导的内皮功能障碍的大鼠血管内皮细胞模型，并发现高糖处理也会增加 STING 的表达。此外，STING 抑制剂 C176 促进糖尿病伤口愈合，而 STING 激动剂 DMXAA 抑制糖尿病伤口愈合。一致地，STING 抑制逆转了 HG 诱导的 CD31 和血管内皮生长因子（VEGF）的减少，抑制了细胞凋亡，并促进了内皮细胞的迁移。值得注意的是，DMXAA 处理本身就足以诱导内皮细胞功能障碍，类似于高糖处理。机制上，STING 通过激活干扰素调节因子 3/核因子 kappa B 通路介导 HG 诱导的血管内皮细胞功能障碍。总之，我们的研究揭示了 DFU 发病机制中内皮 STING 激活介导的分子机制，并确定 STING 是 DFU 的一个新的潜在治疗靶点。
