Objective
Metabolic stress in obesity induces endothelial inflammation and activation, which initiates adipose tissue inflammation, insulin resistance, and cardiovascular diseases. However, the mechanisms underlying endothelial inflammation induction are not completely understood. Stimulator of interferon genes (STING) is an important molecule in immunity and inflammation. In the present study, we sought to determine the role of STING in palmitic acid (PA)-induced endothelial activation/inflammation.
Approach and Results
In cultured endothelial cells, PA treatment activated STING, as indicated by its perinuclear translocation and binding to interferon regulatory factor 3 (IRF3), leading to IRF3 phosphorylation and nuclear translocation. The activated IRF3 bound to the promoter of intercellular adhesion molecule 1 (ICAM-1) and induced ICAM-1 expression and monocyte–endothelial cell adhesion. When analyzing the upstream signaling, we found that PA activated STING by inducing mitochondrial damage. PA treatment caused mitochondrial damage and leakage of mitochondrial DNA (mtDNA) into the cytosol. Through the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), the mitochondrial damage and leaked cytosolic mtDNA activated the STING-IRF3 pathway and increased ICAM-1 expression. In mice with diet-induced obesity, the STING-IRF3 pathway was activated in adipose tissue. However, STING deficiency (Stinggt/gt) partially prevented diet-induced adipose tissue inflammation, obesity, insulin resistance, and glucose intolerance.
Conclusions
The mitochondrial damage-cGAS-STING-IRF3 pathway is critically involved in metabolic stress-induced endothelial inflammation. STING may be a potential therapeutic target for preventing cardiovascular diseases and insulin resistance in obese individuals.
We explored the interactive effects of endothelial nitric oxide synthase (eNOS) genotypes and cigarette smoking on protein levels and enzyme activity in 33 postpartum placentas. Whilst the eNOS protein levels were lower in the rare allele (0.48 þ 0.11, n = 9 vs. 1.05 þ 0.10, n = 24, P 6 0.01), the eNOS enzyme activity was about 7-fold higher in the rare allele (4556.2 þ 255.4 vs. 621.8 þ 180.5 cpm/mg/min, P 6 0.01). Smokers had lower eNOS protein levels (1.07 þ 0.09 vs. 0.50 þ 0.19, P 6 0.05) in both alleles. It reduced the eNOS activities only in the rare allele (non-smokers: 6143.8 þ 251.2, n = 5, smokers: 2968.5 þ 259.4, n = 4, 52% reduction, P 6 0.01). We conclude that associations between eNOS polymorphism and protein levels and enzyme activities are modifiable by smoking, the effects of smoking are dependent on the eNOS genotypes.z 2000 Federation of European Biochemical Societies.
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