ID | 119425 |
Title Alternative | STING and Endothelial Dysfunction
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Author |
Pham, Phuong Tran
Tokushima University|Vanderbilt University
Bavuu, Oyunbileg
Tokushima University
Kim-Kaneyama, Joo-Ri
Showa University
Lei, Xiao-Feng
Showa University
Yamamoto, Takayuki
Osaka Metropolitan University
Otsuka, Kenichiro
Osaka Metropolitan University
Kusunose, Kenya
Tokushima University|University of the Ryukyus
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Yagi, Shusuke
Tokushima University
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Yamada, Hirotsugu
Tokushima University
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Soeki, Takeshi
Tokushima University
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Barber, Glen N.
University of Miami
Sata, Masataka
Tokushima University
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Keywords | diabetes
endothelial function
nflammation
STING
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Content Type |
Journal Article
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Description | 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. |
Journal Title |
Journal of the American Heart Association
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ISSN | 20479980
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Publisher | The American Heart Association
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Volume | 12
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Issue | 22
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Start Page | e030084
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Published Date | 2023-11-10
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Rights | ©2023 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License(https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. JAHA is available at: www.ahajournals.org/journal/jaha
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DOI (Published Version) | |
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language |
eng
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TextVersion |
Publisher
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departments |
University Hospital
Medical Sciences
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