Targeted inhibition of macrophage STING signaling alleviates inflammatory injury and ventricular remodeling in acute myocardial infarction
Mitochondrial DNA (mtDNA) acts as a damage-associated molecular pattern to activate the stimulator of interferon genes (STING) signaling in macrophages, promoting tissue inflammation. However, its role in acute myocardial infarction (AMI) remains unclear. Macrophage-specific Sting1 knockout mice wer...
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| Format: | Article |
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Elsevier
2025-08-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383525004344 |
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| author | Huan Yao Qingman He Shujun Wei Li Xiang Yuanyuan Luo Cong Huang Weiwei Liu Chuan Zheng Xueping Li Yongxiang Gao |
| author_facet | Huan Yao Qingman He Shujun Wei Li Xiang Yuanyuan Luo Cong Huang Weiwei Liu Chuan Zheng Xueping Li Yongxiang Gao |
| author_sort | Huan Yao |
| collection | DOAJ |
| description | Mitochondrial DNA (mtDNA) acts as a damage-associated molecular pattern to activate the stimulator of interferon genes (STING) signaling in macrophages, promoting tissue inflammation. However, its role in acute myocardial infarction (AMI) remains unclear. Macrophage-specific Sting1 knockout mice were used to validate STING's pathological role in AMI. Cardiac and liver mtDNA were used to activate macrophages in co-culture systems with cardiomyocytes to assess fibrosis and hypertrophy. Panaxatriol saponin (PTS) was tested for its ability to block mtDNA-driven macrophage activation and subsequent cardiomyocyte damage. STING–PTS binding ability was analyzed. AMI rats received PTS to evaluate its effects on myocardial inflammation and ventricular remodeling. In vivo, macrophage-specific Sting1 knockout reduced myocardial inflammation and injury after AMI. In vitro, mtDNA-activated macrophages induced cardiomyocyte fibrosis and hypertrophy through STING signaling. PTS suppressed mtDNA-driven macrophage activation by directly binding STING, thereby blocking inflammatory cascades. In AMI rats, PTS treatment attenuated acute inflammation and reversed ventricular remodeling. These findings establish the mtDNA–STING axis in macrophages as a critical driver of post-AMI inflammation and identify pharmacological STING inhibition with PTS as a promising therapeutic strategy. The study bridges genetic validation with translational applications, highlighting macrophage STING as a novel target for ischemic heart disease management. |
| format | Article |
| id | doaj-art-ea13d36729f94844a662f4f7fc8a3fb9 |
| institution | Kabale University |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-ea13d36729f94844a662f4f7fc8a3fb92025-08-20T05:06:37ZengElsevierActa Pharmaceutica Sinica B2211-38352025-08-011584030404610.1016/j.apsb.2025.06.014Targeted inhibition of macrophage STING signaling alleviates inflammatory injury and ventricular remodeling in acute myocardial infarctionHuan Yao0Qingman He1Shujun Wei2Li Xiang3Yuanyuan Luo4Cong Huang5Weiwei Liu6Chuan Zheng7Xueping Li8Yongxiang Gao9Sichuan Provincial Engineering Research Center of Innovative Re-Development of Famous Classical Formulas, Tianfu TCM Innovation Harbour, Chengdu University of Traditional Chinese Medicine, Chengdu 611930, China; Sichuan Provincial Engineering Technology Research Center of Natural Small Molecule Drug, Tianfu TCM Innovation Harbour, Chengdu University of Traditional Chinese Medicine, Chengdu 611930, ChinaHospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, ChinaChengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Sichuan Police College, Luzhou 646000, ChinaHospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, ChinaHospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, ChinaSchool of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaSchool of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, ChinaSichuan Provincial Engineering Technology Research Center of Natural Small Molecule Drug, Tianfu TCM Innovation Harbour, Chengdu University of Traditional Chinese Medicine, Chengdu 611930, China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China; Corresponding authors.Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China; Corresponding authors.Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China; Corresponding authors.Mitochondrial DNA (mtDNA) acts as a damage-associated molecular pattern to activate the stimulator of interferon genes (STING) signaling in macrophages, promoting tissue inflammation. However, its role in acute myocardial infarction (AMI) remains unclear. Macrophage-specific Sting1 knockout mice were used to validate STING's pathological role in AMI. Cardiac and liver mtDNA were used to activate macrophages in co-culture systems with cardiomyocytes to assess fibrosis and hypertrophy. Panaxatriol saponin (PTS) was tested for its ability to block mtDNA-driven macrophage activation and subsequent cardiomyocyte damage. STING–PTS binding ability was analyzed. AMI rats received PTS to evaluate its effects on myocardial inflammation and ventricular remodeling. In vivo, macrophage-specific Sting1 knockout reduced myocardial inflammation and injury after AMI. In vitro, mtDNA-activated macrophages induced cardiomyocyte fibrosis and hypertrophy through STING signaling. PTS suppressed mtDNA-driven macrophage activation by directly binding STING, thereby blocking inflammatory cascades. In AMI rats, PTS treatment attenuated acute inflammation and reversed ventricular remodeling. These findings establish the mtDNA–STING axis in macrophages as a critical driver of post-AMI inflammation and identify pharmacological STING inhibition with PTS as a promising therapeutic strategy. The study bridges genetic validation with translational applications, highlighting macrophage STING as a novel target for ischemic heart disease management.http://www.sciencedirect.com/science/article/pii/S2211383525004344Acute myocardial infarctionMitochondrial DNAMacrophageSTING signalingMyocardial inflammation |
| spellingShingle | Huan Yao Qingman He Shujun Wei Li Xiang Yuanyuan Luo Cong Huang Weiwei Liu Chuan Zheng Xueping Li Yongxiang Gao Targeted inhibition of macrophage STING signaling alleviates inflammatory injury and ventricular remodeling in acute myocardial infarction Acta Pharmaceutica Sinica B Acute myocardial infarction Mitochondrial DNA Macrophage STING signaling Myocardial inflammation |
| title | Targeted inhibition of macrophage STING signaling alleviates inflammatory injury and ventricular remodeling in acute myocardial infarction |
| title_full | Targeted inhibition of macrophage STING signaling alleviates inflammatory injury and ventricular remodeling in acute myocardial infarction |
| title_fullStr | Targeted inhibition of macrophage STING signaling alleviates inflammatory injury and ventricular remodeling in acute myocardial infarction |
| title_full_unstemmed | Targeted inhibition of macrophage STING signaling alleviates inflammatory injury and ventricular remodeling in acute myocardial infarction |
| title_short | Targeted inhibition of macrophage STING signaling alleviates inflammatory injury and ventricular remodeling in acute myocardial infarction |
| title_sort | targeted inhibition of macrophage sting signaling alleviates inflammatory injury and ventricular remodeling in acute myocardial infarction |
| topic | Acute myocardial infarction Mitochondrial DNA Macrophage STING signaling Myocardial inflammation |
| url | http://www.sciencedirect.com/science/article/pii/S2211383525004344 |
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