2. Academic Validation
  3. High glucose-induced endothelial STING activation inhibits diabetic wound healing through impairment of angiogenesis

High glucose-induced endothelial STING activation inhibits diabetic wound healing through impairment of angiogenesis

  • Biochem Biophys Res Commun. 2023 Aug 6:668:82-89. doi: 10.1016/j.bbrc.2023.05.081.
Lifang Luo 1,  Ying An 1,  Kang Geng 2,  Shengrong Wan 2,  Fanjie Zhang 1,  Xiaozhen Tan 1,  Zongzhe Jiang 3,  Yong Xu 4
Affiliations

Affiliations

  • 1 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.
  • 2 Metabolic Vascular Disease Key Laboratory of Sichuan Province, Sichuan, 646000, China; Sichuan Clinical Research Center for Nephropathy, Sichuan, 646000, China.
  • 3 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; Academician (Expert) Workstation of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, China. Electronic address: [email protected].
  • 4 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. Electronic address: [email protected].
PMID: 37245293 DOI: 10.1016/j.bbrc.2023.05.081
Abstract

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.

Keywords

Diabetic wound healing; High glucose; STING.

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