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Original Research

STING–IRF3 Triggers Endothelial Inflammation in Response to Free Fatty Acid-Induced Mitochondrial Damage in Diet-Induced Obesity

Yun Mao, Wei Luo, Lin Zhang, Weiwei Wu, Liangshuai Yuan, Hao Xu, Juhee Song, Keigi Fujiwara, Jun-ichi Abe, Scott A. LeMaire, Xing Li Wang, Ying H. Shen
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https://doi.org/10.1161/ATVBAHA.117.309017
Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;ATVBAHA.117.309017
Originally published March 16, 2017
Yun Mao
From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, China (Y.M., W.L., W.W., L.Y., H.X., X.L.W.); Qilu Hospital of Shandong University, 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.); and 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.
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Wei Luo
From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, China (Y.M., W.L., W.W., L.Y., H.X., X.L.W.); Qilu Hospital of Shandong University, 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.); and 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.
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Lin Zhang
From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, China (Y.M., W.L., W.W., L.Y., H.X., X.L.W.); Qilu Hospital of Shandong University, 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.); and 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.
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Weiwei Wu
From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, China (Y.M., W.L., W.W., L.Y., H.X., X.L.W.); Qilu Hospital of Shandong University, 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.); and 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.
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Liangshuai Yuan
From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, China (Y.M., W.L., W.W., L.Y., H.X., X.L.W.); Qilu Hospital of Shandong University, 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.); and 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.
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Hao Xu
From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, China (Y.M., W.L., W.W., L.Y., H.X., X.L.W.); Qilu Hospital of Shandong University, 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.); and 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.
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Juhee Song
From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, China (Y.M., W.L., W.W., L.Y., H.X., X.L.W.); Qilu Hospital of Shandong University, 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.); and 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.
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Keigi Fujiwara
From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, China (Y.M., W.L., W.W., L.Y., H.X., X.L.W.); Qilu Hospital of Shandong University, 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.); and 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.
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Jun-ichi Abe
From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, China (Y.M., W.L., W.W., L.Y., H.X., X.L.W.); Qilu Hospital of Shandong University, 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.); and 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.
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Scott A. LeMaire
From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, China (Y.M., W.L., W.W., L.Y., H.X., X.L.W.); Qilu Hospital of Shandong University, 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.); and 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.
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Xing Li Wang
From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, China (Y.M., W.L., W.W., L.Y., H.X., X.L.W.); Qilu Hospital of Shandong University, 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.); and 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.
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Ying H. Shen
From the Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, China (Y.M., W.L., W.W., L.Y., H.X., X.L.W.); Qilu Hospital of Shandong University, 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.); and 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.
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This article has a correction. Please see:

  • Correction to: STING–IRF3 Triggers Endothelial Inflammation in Response to Free Fatty Acid-Induced Mitochondrial Damage in Diet-Induced Obesity - April 01, 2018
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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 intercellular adhesion molecule 1 and induced intercellular adhesion molecule-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 cyclic GMP-AMP synthase, the mitochondrial damage and leaked cytosolic mitochondrial DNA activated the STING–IRF3 pathway and increased intercellular adhesion molecule-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-cyclic GMP-AMP synthase–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.

  • diet, high-fat
  • DNA, mitochondrial
  • endothelium
  • palmitic acid
  • vascular diseases
  • Received May 18, 2017.
  • Accepted March 6, 2017.
  • © 2017 American Heart Association, Inc.
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    STING–IRF3 Triggers Endothelial Inflammation in Response to Free Fatty Acid-Induced Mitochondrial Damage in Diet-Induced Obesity
    Yun Mao, Wei Luo, Lin Zhang, Weiwei Wu, Liangshuai Yuan, Hao Xu, Juhee Song, Keigi Fujiwara, Jun-ichi Abe, Scott A. LeMaire, Xing Li Wang and Ying H. Shen
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;ATVBAHA.117.309017, originally published March 16, 2017
    https://doi.org/10.1161/ATVBAHA.117.309017

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    STING–IRF3 Triggers Endothelial Inflammation in Response to Free Fatty Acid-Induced Mitochondrial Damage in Diet-Induced Obesity
    Yun Mao, Wei Luo, Lin Zhang, Weiwei Wu, Liangshuai Yuan, Hao Xu, Juhee Song, Keigi Fujiwara, Jun-ichi Abe, Scott A. LeMaire, Xing Li Wang and Ying H. Shen
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;ATVBAHA.117.309017, originally published March 16, 2017
    https://doi.org/10.1161/ATVBAHA.117.309017
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