Epigenetic modulation of Drp1-mediated mitochondrial fission by inhibition of S-adenosylhomocysteine hydrolase promotes vascular senescence and atherosclerosis
Aims: Vascular senescence, which is closely related to epigenetic regulation, is an early pathological condition in cardiovascular diseases including atherosclerosis. Inhibition of S-adenosylhomocysteine hydrolase (SAHH) and the consequent increase of S-adenosylhomocysteine (SAH), a potent inhibitor...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221323172300229X |
| _version_ | 1797741404246507520 |
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| author | Yiran You Xu Chen Yu Chen Juan Pang Qian Chen Qiannan Liu Hongliang Xue Yupeng Zeng Jinghe Xiao Jiaxin Mi Yi Tang Wenhua Ling |
| author_facet | Yiran You Xu Chen Yu Chen Juan Pang Qian Chen Qiannan Liu Hongliang Xue Yupeng Zeng Jinghe Xiao Jiaxin Mi Yi Tang Wenhua Ling |
| author_sort | Yiran You |
| collection | DOAJ |
| description | Aims: Vascular senescence, which is closely related to epigenetic regulation, is an early pathological condition in cardiovascular diseases including atherosclerosis. Inhibition of S-adenosylhomocysteine hydrolase (SAHH) and the consequent increase of S-adenosylhomocysteine (SAH), a potent inhibitor of DNA methyltransferase, has been associated with an elevated risk of cardiovascular diseases. This study aimed to investigate whether the inhibition of SAHH accelerates vascular senescence and the development of atherosclerosis. Methods and results: The case-control study related to vascular aging showed that increased levels of plasma SAH were positively associated with the risk of vascular aging, with an odds ratio (OR) of 3.90 (95% CI, 1.17–13.02). Elevated pulse wave velocity, impaired endothelium-dependent relaxation response, and increased senescence-associated β-galactosidase staining were observed in the artery of SAHH+/- mice at 32 weeks of age. Additionally, elevated expression of p16, p21, and p53, fission morphology of mitochondria, and over-upregulated expression of Drp1 were observed in vascular endothelial cells with SAHH inhibition in vitro and in vivo. Further downregulation of Drp1 using siRNA or its specific inhibitor, mdivi-1, restored the abnormal mitochondrial morphology and rescued the phenotypes of vascular senescence. Furthermore, inhibition of SAHH in APOE−/− mice promoted vascular senescence and atherosclerosis progression, which was attenuated by mdivi-1 treatment. Mechanistically, hypomethylation over the promoter region of DRP1 and downregulation of DNMT1 were demonstrated with SAHH inhibition in HUVECs. Conclusions: SAHH inhibition epigenetically upregulates Drp1 expression through repressing DNA methylation in endothelial cells, leading to vascular senescence and atherosclerosis. These results identify SAHH or SAH as a potential therapeutic target for vascular senescence and cardiovascular diseases. |
| first_indexed | 2024-03-12T14:27:15Z |
| format | Article |
| id | doaj.art-53800576742b410d9d9d635bf7d44a25 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-03-12T14:27:15Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-53800576742b410d9d9d635bf7d44a252023-08-18T04:31:06ZengElsevierRedox Biology2213-23172023-09-0165102828Epigenetic modulation of Drp1-mediated mitochondrial fission by inhibition of S-adenosylhomocysteine hydrolase promotes vascular senescence and atherosclerosisYiran You0Xu Chen1Yu Chen2Juan Pang3Qian Chen4Qiannan Liu5Hongliang Xue6Yupeng Zeng7Jinghe Xiao8Jiaxin Mi9Yi Tang10Wenhua Ling11Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of ChinaDepartment of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, USADepartment of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of ChinaDepartment of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of ChinaDepartment of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China; School of Public Health and Management, Ningxia Medical University, Yinchuan, People's Republic of ChinaDepartment of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of ChinaDepartment of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of ChinaDepartment of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of ChinaDepartment of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of ChinaDepartment of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of ChinaDepartment of Nutrition, The First People's Hospital of Zhaoqing, Zhaoqing, ChinaDepartment of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China; School of Public Health and Management, Ningxia Medical University, Yinchuan, People's Republic of China; Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, People's Republic of China; Corresponding author. School of Public Health, Sun Yat-Sen University (Northern Campus), No.74, 2nd Zhongshan Road, Guangzhou, 510080, PR China.Aims: Vascular senescence, which is closely related to epigenetic regulation, is an early pathological condition in cardiovascular diseases including atherosclerosis. Inhibition of S-adenosylhomocysteine hydrolase (SAHH) and the consequent increase of S-adenosylhomocysteine (SAH), a potent inhibitor of DNA methyltransferase, has been associated with an elevated risk of cardiovascular diseases. This study aimed to investigate whether the inhibition of SAHH accelerates vascular senescence and the development of atherosclerosis. Methods and results: The case-control study related to vascular aging showed that increased levels of plasma SAH were positively associated with the risk of vascular aging, with an odds ratio (OR) of 3.90 (95% CI, 1.17–13.02). Elevated pulse wave velocity, impaired endothelium-dependent relaxation response, and increased senescence-associated β-galactosidase staining were observed in the artery of SAHH+/- mice at 32 weeks of age. Additionally, elevated expression of p16, p21, and p53, fission morphology of mitochondria, and over-upregulated expression of Drp1 were observed in vascular endothelial cells with SAHH inhibition in vitro and in vivo. Further downregulation of Drp1 using siRNA or its specific inhibitor, mdivi-1, restored the abnormal mitochondrial morphology and rescued the phenotypes of vascular senescence. Furthermore, inhibition of SAHH in APOE−/− mice promoted vascular senescence and atherosclerosis progression, which was attenuated by mdivi-1 treatment. Mechanistically, hypomethylation over the promoter region of DRP1 and downregulation of DNMT1 were demonstrated with SAHH inhibition in HUVECs. Conclusions: SAHH inhibition epigenetically upregulates Drp1 expression through repressing DNA methylation in endothelial cells, leading to vascular senescence and atherosclerosis. These results identify SAHH or SAH as a potential therapeutic target for vascular senescence and cardiovascular diseases.http://www.sciencedirect.com/science/article/pii/S221323172300229Xvascular senescenceAtherosclerosisS-adenosylhomocysteine hydrolaseDNA methylationmitochondrial dynamics |
| spellingShingle | Yiran You Xu Chen Yu Chen Juan Pang Qian Chen Qiannan Liu Hongliang Xue Yupeng Zeng Jinghe Xiao Jiaxin Mi Yi Tang Wenhua Ling Epigenetic modulation of Drp1-mediated mitochondrial fission by inhibition of S-adenosylhomocysteine hydrolase promotes vascular senescence and atherosclerosis Redox Biology vascular senescence Atherosclerosis S-adenosylhomocysteine hydrolase DNA methylation mitochondrial dynamics |
| title | Epigenetic modulation of Drp1-mediated mitochondrial fission by inhibition of S-adenosylhomocysteine hydrolase promotes vascular senescence and atherosclerosis |
| title_full | Epigenetic modulation of Drp1-mediated mitochondrial fission by inhibition of S-adenosylhomocysteine hydrolase promotes vascular senescence and atherosclerosis |
| title_fullStr | Epigenetic modulation of Drp1-mediated mitochondrial fission by inhibition of S-adenosylhomocysteine hydrolase promotes vascular senescence and atherosclerosis |
| title_full_unstemmed | Epigenetic modulation of Drp1-mediated mitochondrial fission by inhibition of S-adenosylhomocysteine hydrolase promotes vascular senescence and atherosclerosis |
| title_short | Epigenetic modulation of Drp1-mediated mitochondrial fission by inhibition of S-adenosylhomocysteine hydrolase promotes vascular senescence and atherosclerosis |
| title_sort | epigenetic modulation of drp1 mediated mitochondrial fission by inhibition of s adenosylhomocysteine hydrolase promotes vascular senescence and atherosclerosis |
| topic | vascular senescence Atherosclerosis S-adenosylhomocysteine hydrolase DNA methylation mitochondrial dynamics |
| url | http://www.sciencedirect.com/science/article/pii/S221323172300229X |
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