Phuong Tran Pham1, Daiju Fukuda1,2, Sachiko Nishimoto1,3, Joo-Ri Kim-Kaneyama4, Xiao-Feng Lei4, Yutaka Takahashi5,6, Tomohito Sato5, Kimie Tanaka7, Kumiko Suto1, Yutaka Kawabata1, Koji Yamaguchi1, Shusuke Yagi1, Kenya Kusunose1, Hirotsugu Yamada8, Takeshi Soeki1, Tetsuzo Wakatsuki1, Kenji Shimada9, Yasuhisa Kanematsu9, Yasushi Takagi9, Michio Shimabukuro2,10, Mitsutoshi Setou5, Glen N Barber11, Masataka Sata1. 1. Department of Cardiovascular Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-Cho, Tokushima 770-8503, Japan. 2. Department of Cardio-Diabetes Medicine, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-Cho, Tokushima 770-8503, Japan. 3. Faculty of Clinical Nutrition and Dietetics, Konan Women's University, 6-2-23, Morikita-machi, Higashinada-ku, Kobe 658-0001, Japan. 4. Department of Biochemistry, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan. 5. Department of Cellular and Molecular Anatomy, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan. 6. Preppers, Co., Ltd, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Tokyo 140-001, Japan. 7. Division for Health Service Promotion, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. 8. Department of Community Medicine for Cardiology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-Cho, Tokushima, 770-8503, Japan. 9. Department of Neurosurgery, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-Cho, Tokushima 770-8503, Japan. 10. Department of Diabetes, Endocrinology and Metabolism, School of Medicine, 1 Hikariga-oka, Fukushima 960-1295, Japan. 11. Department of Cell Biology, University of Miami Miller School of Medicine, 1550 NW 10th Avenue, PAP 5th floor Miami, Florida 33136, USA.
Abstract
AIMS: Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis. METHODS AND RESULTS: Apolipoprotein E-deficient (Apoe-/-) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe-/- mice. Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe-/- mice. In contrast, bone marrow-specific STING expression in Apoe-/- mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-β) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP. CONCLUSION: Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis. METHODS AND RESULTS: Apolipoprotein E-deficient (Apoe-/-) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe-/- mice. Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe-/- mice. In contrast, bone marrow-specific STING expression in Apoe-/- mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-β) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP. CONCLUSION: Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Yao Du; Hui Zhang; Xiaoyan Nie; Yajun Qi; Shi Shi; Yingying Han; Wenchen Zhou; Chaoyong He; Lintao Wang Journal: Front Cardiovasc Med Date: 2022-08-22