2. Academic Validation
  3. Epigenetic modulation of Drp1-mediated mitochondrial fission by inhibition of S-adenosylhomocysteine hydrolase promotes vascular senescence and atherosclerosis

Epigenetic modulation of Drp1-mediated mitochondrial fission by inhibition of S-adenosylhomocysteine hydrolase promotes vascular senescence and atherosclerosis

  • Redox Biol. 2023 Jul 25;65:102828. doi: 10.1016/j.redox.2023.102828.
Yiran You 1,  Xu Chen 2,  Yu Chen 1,  Juan Pang 1,  Qian Chen 3,  Qiannan Liu 1,  Hongliang Xue 1,  Yupeng Zeng 1,  Jinghe Xiao 1,  Jiaxin Mi 1,  Yi Tang 4,  Wenhua Ling 5
Affiliations

Affiliations

  • 1 Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China.
  • 2 Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, USA.
  • 3 Department 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 China.
  • 4 Department of Nutrition, The First People's Hospital of Zhaoqing, Zhaoqing, China.
  • 5 Department 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. Electronic address: [email protected].
PMID: 37517319 DOI: 10.1016/j.redox.2023.102828
Abstract

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.

Keywords

Atherosclerosis; DNA methylation; S-adenosylhomocysteine hydrolase; mitochondrial dynamics; vascular senescence.

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