Mitochondrial damage and activation of the cytosolic DNA sensor cGAS–STING pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy mice
Abstract Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks specific treatment. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been suggested to contribute to the pathogenesis of cardiovascular diseases. H...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-05-01
|
| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-022-01046-w |
| _version_ | 1811235494870122496 |
|---|---|
| author | Meiling Yan Yun Li Qingmao Luo Wenru Zeng Xiaoqi Shao Lun Li Qing Wang Dongwei Wang Yue Zhang Hongtao Diao Xianglu Rong Yunlong Bai Jiao Guo |
| author_facet | Meiling Yan Yun Li Qingmao Luo Wenru Zeng Xiaoqi Shao Lun Li Qing Wang Dongwei Wang Yue Zhang Hongtao Diao Xianglu Rong Yunlong Bai Jiao Guo |
| author_sort | Meiling Yan |
| collection | DOAJ |
| description | Abstract Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks specific treatment. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been suggested to contribute to the pathogenesis of cardiovascular diseases. However, whether cGAS-STING is involved in the development of DCM has not been established. Our study aimed to determine the role of cGAS-STING in the initiation of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome-induced cardiac pyroptosis and chronic inflammation during the pathogenesis of DCM. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically knock down myocardial STING. After four weeks, mice with myocardium-specific knockdown of STING received injections of streptozotocin (STZ; 50 mg/kg) and a high-fat diet to induce diabetes. Measurements included echocardiography, immunohistochemical analyses, wheat germ agglutinin (WGA) staining, and western blotting. Here, we showed that the cGAS-STING signaling pathway was activated in diabetic hearts, which was indicated by the increased phosphorylation of TANK-binding kinase 1 (TBK1) and interferon (IFN) regulatory factor 3 (IRF3), leading to the activation of the NLRP3 inflammasome in the hearts of diabetic mice and proinflammatory cytokine release into serum. Moreover, STING knockdown via adeno-associated virus-9 (AAV9) in diabetic mouse heart alleviated cardiac pyroptosis and the inflammatory response, prevented diabetes-induced hypertrophy, and restored cardiac function. Mechanistically, we showed that palmitic acid (PA)-induced lipotoxicity impairs mitochondrial homeostasis, producing excessive mitochondrial reactive oxygen species (mtROS), which results in oxidative damage to mitochondrial DNA (mtDNA) and its release into the cytoplasm while switching on cGAS-STING-mediated pyroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy. Our study demonstrated that activation of the cGAS-STING pathway caused by mitochondrial oxidative damage and mtDNA escape induced by free fatty acids promoted pyroptosis and proinflammatory responses in cardiomyocytes in a NLRP3 inflammasome-dependent manner, thus promoting myocardial hypertrophy during the progression of DCM. |
| first_indexed | 2024-04-12T11:52:49Z |
| format | Article |
| id | doaj.art-af0ac83ceac34948bf34881beb37af90 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-12T11:52:49Z |
| publishDate | 2022-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-af0ac83ceac34948bf34881beb37af902022-12-22T03:34:08ZengNature Publishing GroupCell Death Discovery2058-77162022-05-018111210.1038/s41420-022-01046-wMitochondrial damage and activation of the cytosolic DNA sensor cGAS–STING pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy miceMeiling Yan0Yun Li1Qingmao Luo2Wenru Zeng3Xiaoqi Shao4Lun Li5Qing Wang6Dongwei Wang7Yue Zhang8Hongtao Diao9Xianglu Rong10Yunlong Bai11Jiao Guo12The Center for Drug Research and Development, Guangdong Pharmaceutical UniversityThe Center for Drug Research and Development, Guangdong Pharmaceutical UniversityThe Center for Drug Research and Development, Guangdong Pharmaceutical UniversityThe Center for Drug Research and Development, Guangdong Pharmaceutical UniversityThe Center for Drug Research and Development, Guangdong Pharmaceutical UniversityThe Center for Drug Research and Development, Guangdong Pharmaceutical UniversityThe Center for Drug Research and Development, Guangdong Pharmaceutical UniversityThe Center for Drug Research and Development, Guangdong Pharmaceutical UniversityThe Center for Drug Research and Development, Guangdong Pharmaceutical UniversityThe Center for Drug Research and Development, Guangdong Pharmaceutical UniversityGuangdong Metabolic Disease Research Center of Integrated Chinese and Western MedicineDepartment of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical UniversityGuangdong Metabolic Disease Research Center of Integrated Chinese and Western MedicineAbstract Diabetic cardiomyopathy (DCM) is a serious cardiac complication of diabetes that currently lacks specific treatment. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been suggested to contribute to the pathogenesis of cardiovascular diseases. However, whether cGAS-STING is involved in the development of DCM has not been established. Our study aimed to determine the role of cGAS-STING in the initiation of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome-induced cardiac pyroptosis and chronic inflammation during the pathogenesis of DCM. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically knock down myocardial STING. After four weeks, mice with myocardium-specific knockdown of STING received injections of streptozotocin (STZ; 50 mg/kg) and a high-fat diet to induce diabetes. Measurements included echocardiography, immunohistochemical analyses, wheat germ agglutinin (WGA) staining, and western blotting. Here, we showed that the cGAS-STING signaling pathway was activated in diabetic hearts, which was indicated by the increased phosphorylation of TANK-binding kinase 1 (TBK1) and interferon (IFN) regulatory factor 3 (IRF3), leading to the activation of the NLRP3 inflammasome in the hearts of diabetic mice and proinflammatory cytokine release into serum. Moreover, STING knockdown via adeno-associated virus-9 (AAV9) in diabetic mouse heart alleviated cardiac pyroptosis and the inflammatory response, prevented diabetes-induced hypertrophy, and restored cardiac function. Mechanistically, we showed that palmitic acid (PA)-induced lipotoxicity impairs mitochondrial homeostasis, producing excessive mitochondrial reactive oxygen species (mtROS), which results in oxidative damage to mitochondrial DNA (mtDNA) and its release into the cytoplasm while switching on cGAS-STING-mediated pyroptosis in cardiomyocytes, thereby worsening the progression of diabetic cardiomyopathy. Our study demonstrated that activation of the cGAS-STING pathway caused by mitochondrial oxidative damage and mtDNA escape induced by free fatty acids promoted pyroptosis and proinflammatory responses in cardiomyocytes in a NLRP3 inflammasome-dependent manner, thus promoting myocardial hypertrophy during the progression of DCM.https://doi.org/10.1038/s41420-022-01046-w |
| spellingShingle | Meiling Yan Yun Li Qingmao Luo Wenru Zeng Xiaoqi Shao Lun Li Qing Wang Dongwei Wang Yue Zhang Hongtao Diao Xianglu Rong Yunlong Bai Jiao Guo Mitochondrial damage and activation of the cytosolic DNA sensor cGAS–STING pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy mice Cell Death Discovery |
| title | Mitochondrial damage and activation of the cytosolic DNA sensor cGAS–STING pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy mice |
| title_full | Mitochondrial damage and activation of the cytosolic DNA sensor cGAS–STING pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy mice |
| title_fullStr | Mitochondrial damage and activation of the cytosolic DNA sensor cGAS–STING pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy mice |
| title_full_unstemmed | Mitochondrial damage and activation of the cytosolic DNA sensor cGAS–STING pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy mice |
| title_short | Mitochondrial damage and activation of the cytosolic DNA sensor cGAS–STING pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy mice |
| title_sort | mitochondrial damage and activation of the cytosolic dna sensor cgas sting pathway lead to cardiac pyroptosis and hypertrophy in diabetic cardiomyopathy mice |
| url | https://doi.org/10.1038/s41420-022-01046-w |
| work_keys_str_mv | AT meilingyan mitochondrialdamageandactivationofthecytosolicdnasensorcgasstingpathwayleadtocardiacpyroptosisandhypertrophyindiabeticcardiomyopathymice AT yunli mitochondrialdamageandactivationofthecytosolicdnasensorcgasstingpathwayleadtocardiacpyroptosisandhypertrophyindiabeticcardiomyopathymice AT qingmaoluo mitochondrialdamageandactivationofthecytosolicdnasensorcgasstingpathwayleadtocardiacpyroptosisandhypertrophyindiabeticcardiomyopathymice AT wenruzeng mitochondrialdamageandactivationofthecytosolicdnasensorcgasstingpathwayleadtocardiacpyroptosisandhypertrophyindiabeticcardiomyopathymice AT xiaoqishao mitochondrialdamageandactivationofthecytosolicdnasensorcgasstingpathwayleadtocardiacpyroptosisandhypertrophyindiabeticcardiomyopathymice AT lunli mitochondrialdamageandactivationofthecytosolicdnasensorcgasstingpathwayleadtocardiacpyroptosisandhypertrophyindiabeticcardiomyopathymice AT qingwang mitochondrialdamageandactivationofthecytosolicdnasensorcgasstingpathwayleadtocardiacpyroptosisandhypertrophyindiabeticcardiomyopathymice AT dongweiwang mitochondrialdamageandactivationofthecytosolicdnasensorcgasstingpathwayleadtocardiacpyroptosisandhypertrophyindiabeticcardiomyopathymice AT yuezhang mitochondrialdamageandactivationofthecytosolicdnasensorcgasstingpathwayleadtocardiacpyroptosisandhypertrophyindiabeticcardiomyopathymice AT hongtaodiao mitochondrialdamageandactivationofthecytosolicdnasensorcgasstingpathwayleadtocardiacpyroptosisandhypertrophyindiabeticcardiomyopathymice AT xianglurong mitochondrialdamageandactivationofthecytosolicdnasensorcgasstingpathwayleadtocardiacpyroptosisandhypertrophyindiabeticcardiomyopathymice AT yunlongbai mitochondrialdamageandactivationofthecytosolicdnasensorcgasstingpathwayleadtocardiacpyroptosisandhypertrophyindiabeticcardiomyopathymice AT jiaoguo mitochondrialdamageandactivationofthecytosolicdnasensorcgasstingpathwayleadtocardiacpyroptosisandhypertrophyindiabeticcardiomyopathymice |