Cigarette tar accelerates atherosclerosis progression via RIPK3-dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cells
Abstract Background Tar is the main toxic of cigarettes, and its effect on atherosclerosis progression and the underlying mechanisms remain largely unknown. Vascular smooth muscle cells (VSMCs) play a key role in atherogenesis and plaque vulnerability. The present study sought to investigate the mec...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-01-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-024-01480-6 |
| _version_ | 1797349772401573888 |
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| author | Xiaoxuan Bai Ying Wang Xing Luo Xiaoyi Bao Xiuzhu Weng Yuwu Chen Shan Zhang Ying Lv Xinyu Dai Ming Zeng Dan Yang Sining Hu Ji Li Yong Ji Haibo Jia Bo Yu |
| author_facet | Xiaoxuan Bai Ying Wang Xing Luo Xiaoyi Bao Xiuzhu Weng Yuwu Chen Shan Zhang Ying Lv Xinyu Dai Ming Zeng Dan Yang Sining Hu Ji Li Yong Ji Haibo Jia Bo Yu |
| author_sort | Xiaoxuan Bai |
| collection | DOAJ |
| description | Abstract Background Tar is the main toxic of cigarettes, and its effect on atherosclerosis progression and the underlying mechanisms remain largely unknown. Vascular smooth muscle cells (VSMCs) play a key role in atherogenesis and plaque vulnerability. The present study sought to investigate the mechanism of atherosclerosis progression through tar-induced VSMC necroptosis, a recently described form of necrosis. Methods The effect of tar on atherosclerosis progression and VSMC necroptosis was examined in ApoE−/− mice and cultured VSMCs. The role of necroptosis in tar-induced plaque development was evaluated in RIPK3-deletion mice (ApoE−/−RIPK3−/−). The key proteins of necroptosis in carotid plaques of smokers and non-smokers were also examined. Quantitative proteomics of mice aortas was conducted to further investigate the underlying mechanism. Pharmacological approaches were then applied to modulate the expression of targets to verify the regulatory process of tar-induced necroptosis. Results Tar administration led to increased atherosclerotic plaque area and reduced collagen and VSMCs in ApoE−/− mice. The expression of RIPK1、RIPK3、and MLKL in VSMCs of plaques were all increased in tar-exposed mice and smokers. RIPK3 deletion protected against VSMC loss and plaque progression stimulated by tar. In mechanistic studies, quantitative proteomics analysis of ApoE−/− mice aortas suggested that tar triggered endoplasmic reticulum (ER) stress. PERK-eIF2α-CHOP axis was activated in tar-treated VSMCs and atherosclerotic plaque. Inhibition of ER stress using 4PBA significantly reduced plaque progression and VSMC necroptosis. Further study revealed that ER stress resulted in calcium (Ca2+) release into mitochondria and cytoplasm. Elevated Ca2+ levels lead to mitochondrial dysfunction and excessive reactive oxygen species (ROS) production, which consequently promote RIPK3-dependent necroptosis. In addition, Ca2+/calmodulin-dependent protein kinase II (CaMKII) activated by cytosolic Ca2+ overload binds to RIPK3, accounting for necroptosis. Conclusion The findings revealed that cigarette tar promoted atherosclerosis progression by inducing RIPK3-dependent VSMC necroptosis and identified novel avenues of ER stress and Ca2+ overload. |
| first_indexed | 2024-03-08T12:35:16Z |
| format | Article |
| id | doaj.art-450dc22476764445a58052796b3ca6ca |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-03-08T12:35:16Z |
| publishDate | 2024-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-450dc22476764445a58052796b3ca6ca2024-01-21T12:28:22ZengBMCCell Communication and Signaling1478-811X2024-01-0122111810.1186/s12964-024-01480-6Cigarette tar accelerates atherosclerosis progression via RIPK3-dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cellsXiaoxuan Bai0Ying Wang1Xing Luo2Xiaoyi Bao3Xiuzhu Weng4Yuwu Chen5Shan Zhang6Ying Lv7Xinyu Dai8Ming Zeng9Dan Yang10Sining Hu11Ji Li12Yong Ji13Haibo Jia14Bo Yu15Department of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Forensic Medicine, Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityNational Key Laboratory of Frigid Zone Cardiovascular Diseases, Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Harbin Medical UniversityAbstract Background Tar is the main toxic of cigarettes, and its effect on atherosclerosis progression and the underlying mechanisms remain largely unknown. Vascular smooth muscle cells (VSMCs) play a key role in atherogenesis and plaque vulnerability. The present study sought to investigate the mechanism of atherosclerosis progression through tar-induced VSMC necroptosis, a recently described form of necrosis. Methods The effect of tar on atherosclerosis progression and VSMC necroptosis was examined in ApoE−/− mice and cultured VSMCs. The role of necroptosis in tar-induced plaque development was evaluated in RIPK3-deletion mice (ApoE−/−RIPK3−/−). The key proteins of necroptosis in carotid plaques of smokers and non-smokers were also examined. Quantitative proteomics of mice aortas was conducted to further investigate the underlying mechanism. Pharmacological approaches were then applied to modulate the expression of targets to verify the regulatory process of tar-induced necroptosis. Results Tar administration led to increased atherosclerotic plaque area and reduced collagen and VSMCs in ApoE−/− mice. The expression of RIPK1、RIPK3、and MLKL in VSMCs of plaques were all increased in tar-exposed mice and smokers. RIPK3 deletion protected against VSMC loss and plaque progression stimulated by tar. In mechanistic studies, quantitative proteomics analysis of ApoE−/− mice aortas suggested that tar triggered endoplasmic reticulum (ER) stress. PERK-eIF2α-CHOP axis was activated in tar-treated VSMCs and atherosclerotic plaque. Inhibition of ER stress using 4PBA significantly reduced plaque progression and VSMC necroptosis. Further study revealed that ER stress resulted in calcium (Ca2+) release into mitochondria and cytoplasm. Elevated Ca2+ levels lead to mitochondrial dysfunction and excessive reactive oxygen species (ROS) production, which consequently promote RIPK3-dependent necroptosis. In addition, Ca2+/calmodulin-dependent protein kinase II (CaMKII) activated by cytosolic Ca2+ overload binds to RIPK3, accounting for necroptosis. Conclusion The findings revealed that cigarette tar promoted atherosclerosis progression by inducing RIPK3-dependent VSMC necroptosis and identified novel avenues of ER stress and Ca2+ overload.https://doi.org/10.1186/s12964-024-01480-6Cigarette tarAtherosclerosisVascular smooth muscle cellNecroptosisEndoplasmic reticulum stress |
| spellingShingle | Xiaoxuan Bai Ying Wang Xing Luo Xiaoyi Bao Xiuzhu Weng Yuwu Chen Shan Zhang Ying Lv Xinyu Dai Ming Zeng Dan Yang Sining Hu Ji Li Yong Ji Haibo Jia Bo Yu Cigarette tar accelerates atherosclerosis progression via RIPK3-dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cells Cell Communication and Signaling Cigarette tar Atherosclerosis Vascular smooth muscle cell Necroptosis Endoplasmic reticulum stress |
| title | Cigarette tar accelerates atherosclerosis progression via RIPK3-dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cells |
| title_full | Cigarette tar accelerates atherosclerosis progression via RIPK3-dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cells |
| title_fullStr | Cigarette tar accelerates atherosclerosis progression via RIPK3-dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cells |
| title_full_unstemmed | Cigarette tar accelerates atherosclerosis progression via RIPK3-dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cells |
| title_short | Cigarette tar accelerates atherosclerosis progression via RIPK3-dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cells |
| title_sort | cigarette tar accelerates atherosclerosis progression via ripk3 dependent necroptosis mediated by endoplasmic reticulum stress in vascular smooth muscle cells |
| topic | Cigarette tar Atherosclerosis Vascular smooth muscle cell Necroptosis Endoplasmic reticulum stress |
| url | https://doi.org/10.1186/s12964-024-01480-6 |
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