Innate Immune System Regulated by Stimulator of Interferon Genes, a Cytosolic DNA Sensor, Regulates Endothelial Function

Abstract

Background Sterile inflammation caused by metabolic disorders impairs endothelial function; however, the underlying mechanism by which hyperglycemia induces inflammation remains obscure. Recent studies have suggested that stimulator of interferon genes (STING), a key cytosolic DNA sensor in the innate immune system, contributes to the pathogenesis of inflammatory diseases. This study examines the role of the STING in endothelial dysfunction in streptozotocin‐induced diabetic mice. Methods and Results Injection of streptozotocin promoted the expression of STING and DNA damage markers in the aorta of wild‐type mice. Streptozotocin elevated blood glucose and lipid levels in both wild‐type and STING‐deficient mice, which showed no statistical differences. Genetic deletion of STING ameliorated endothelial dysfunction as determined by the vascular relaxation in response to acetylcholine (P<0.001) and increased endothelial nitric oxide synthase phosphorylation in the aorta (P<0.05) in STZ‐injected mice. Endothelium‐independent vascular response to sodium nitroprusside did not differ. Treatment with a direct STING agonist, cyclic GMP‐AMP, or mitochondrial DNA increased inflammatory molecule expression (eg, VCAM1 and IFNB) and decreased endothelial nitric oxide synthase phosphorylation in human umbilical vein endothelial cells, partially through the STING pathway. Cyclic GMP‐AMP significantly impaired endothelial function of aortic segments obtained from wild‐type mice, which was ameliorated in the presence of C‐176, a STING inhibitor, or a neutralizing interferon‐β antibody. Furthermore, the administration of C‐176 ameliorated endothelial dysfunction in STZ‐induced diabetic mice (P<0.01). Conclusions The DNA damage response regulated by STING impairs endothelial function. STING signaling may be a potential therapeutic target of endothelial dysfunction caused by hyperglycemia.

Keywords

• diabetes
• endothelial function
• inflammation
• STING