Yun Mao1, Wei Luo1, Lin Zhang1, Weiwei Wu1, Liangshuai Yuan1, Hao Xu1, Juhee Song1, Keigi Fujiwara1, Jun-Ichi Abe1, Scott A LeMaire1, Xing Li Wang1, Ying H Shen2. 1. From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston. 2. From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research (Y.M., W.L., W.W., L.Y., H.X., X.L.W.), Jinan, P.R. China; Department of Surgery, Baylor College of Medicine, Houston, TX (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Surgery, Texas Heart Institute, Houston (Y.M., W.L., L.Z., S.A.L., X.L.W., Y.H.S.); Department of Biostatistics (J.S.) and Division of Internal Medicine, Department of Cardiology - Research (K.F., J.-I.A.), The University of Texas MD Anderson Cancer Center, Houston. xingliwang@sdu.edu.cn.
Abstract
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-induced endothelial activation/inflammation. APPROACH AND RESULTS: In cultured endothelial cells, palmitic acid 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 ICAM-1 (intercellular adhesion molecule 1) and induced ICAM-1 expression and monocyte-endothelial cell adhesion. When analyzing the upstream signaling, we found that palmitic acid activated STING by inducing mitochondrial damage. Palmitic acid treatment caused mitochondrial damage and leakage of mitochondrial DNA into the cytosol. Through the cytosolic DNA sensor cGAS (cyclic GMP-AMP synthase), the mitochondrial damage and leaked cytosolic mitochondrial DNA 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.
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-induced endothelial activation/inflammation. APPROACH AND RESULTS: In cultured endothelial cells, palmitic acid 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 ICAM-1 (intercellular adhesion molecule 1) and induced ICAM-1 expression and monocyte-endothelial cell adhesion. When analyzing the upstream signaling, we found that palmitic acid activated STING by inducing mitochondrial damage. Palmitic acid treatment caused mitochondrial damage and leakage of mitochondrial DNA into the cytosol. Through the cytosolic DNA sensor cGAS (cyclic GMP-AMP synthase), themitochondrial damage and leaked cytosolic mitochondrial DNA activated theSTING-IRF3 pathway and increased ICAM-1 expression. In mice with diet-induced obesity, theSTING-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: Themitochondrial 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.
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