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Inhibition of S-adenosylhomocysteine hydrolase induces endothelial senescence via hTERT downregulation

  • Author Footnotes
    1 These authors contributed equally to this article.
    Yiran You
    Footnotes
    1 These authors contributed equally to this article.
    Affiliations
    Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
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  • Author Footnotes
    1 These authors contributed equally to this article.
    Xiaoyuan Sun
    Footnotes
    1 These authors contributed equally to this article.
    Affiliations
    Department of Clinical Nutrition, Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, People's Republic of China
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  • Author Footnotes
    1 These authors contributed equally to this article.
    Jinghe Xiao
    Footnotes
    1 These authors contributed equally to this article.
    Affiliations
    Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
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  • Yu Chen
    Affiliations
    Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
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  • Xu Chen
    Affiliations
    Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
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  • Juan Pang
    Affiliations
    Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
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  • Jiaxin Mi
    Affiliations
    Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
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  • Yi Tang
    Affiliations
    Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
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  • Qiannan Liu
    Affiliations
    Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
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  • Wenhua Ling
    Correspondence
    Corresponding author. School of Public Health, Sun Yat-Sen University (Northern Campus) No.74, 2nd Zhongshan Road, Guangzhou, 510080, People's Republic of China.
    Affiliations
    Department of Nutrition, School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China

    Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, People's Republic of China
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  • Author Footnotes
    1 These authors contributed equally to this article.

      Highlights

      • Inhibition of S-adenosylhomocysteine induces endothelial senescence.
      • Endothelial senescence induced by inhibition of S-adenosylhomocysteine depends on hTERT downregulation.
      • Inhibition of S-adenosylhomocysteine attenuates H3K4me3 occupancy over the hTERT promoter region.

      Abstract

      Background and aims

      It has been established that endothelial senescence plays a critical role in the development of atherosclerosis. Elevated S-adenosylhomocysteine (SAH) level induced by inhibition of S-adenosylhomocysteine hydrolase (SAHH) is one of the risk factors of atherosclerosis; however, the interplay between endothelial senescence and inhibition of SAHH is largely unknown.

      Methods

      Human umbilical vein endothelial cells (HUVECs) after serial passage were used. SAHH-specific inhibitor adenosine dialdehyde (ADA) and SAHH siRNA treated HUVECs and SAHH+/-mice were used to investigate the effect of SAHH inhibition on endothelial senescence.

      Results

      HUVECs exhibited distinct senescence morphology as HUVECs were passaged, together with a decrease in intracellular SAHH expression and an increase in intracellular SAH levels. SAHH inhibition by ADA or SAHH siRNA elevated SA β-gal activity, arrested proliferation, and increased the expression of p16, p21 and p53 in HUVECs and the aortas of mice. In addition, decreased expression of hTERT and reduced occupancy of H3K4me3 over the hTERT promoter region were observed following SAHH inhibition treatment. To further verify the role of hTERT in the endothelial senescence induced by SAHH inhibition, hTERT was overexpressed with a plasmid vector under CMV promoter. hTERT overexpression rescued the senescence phenotypes in endothelial cells induced by SAHH inhibition.

      Conclusions

      SAHH inhibition induces endothelial senescence via downregulation of hTERT expression, which is associated with attenuated histone methylation over the hTERT promoter region.

      Graphical abstract

      Keywords

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