Down-regulation of dihydrofolate reductase inhibits the growth of endothelial EA.hy926 cell through induction of G1 cell cycle arrest via up-regulating p53 and p21^waf1/cip1 expression

• Fei Zhewei

  Department of General Surgery, Xinhua Hospital (Chong Ming) affiliated to Shanghai Jiaotong University School of Medicine

• Gao Yong

  Department of Vascular Surgery, The First Affiliated Hospital of Bengbu Medical College

• Qiu Mingke

  Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine

• Qi Xianqin

  Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine

• Dai Yuxin

  Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine

• Wang Shuqing

  Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine

• Quan Zhiwei

  Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine

• Liu Yingbin

  Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine

• Ou Jingmin

  Department of General Surgery, Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine

抄録

Folic acid supplementation may meliorate cardiovascular disease risk by improving vascular endothelial structure and function. However, the underlying mechanisms are still lack of a global understanding. To be used, folic acid must be converted to 7,8-dihydrofolate by dihydrofolate reductase to generate one-carbon derivatives serving as important cellular cofactors in the synthesis of nucleotides and amino acids required for cell growth. Therefore, this study explored the effect of dihydrofolate reductase knockdown on endothelial EA.hy926 cell growth and the mechanism involved. We found that down-regulation of dihydrofolate reductase inhibited EA.hy926 cell proliferation, and induced G1 phase arrest. Meanwhile, the expression of regulators necessary for G1/S phase transition, such as cyclin-dependent kinases CDK2, CDK4 and CDK6, were remarkably down-regulated; by contrast, the cell cycle inhibitors p21^waf/cip1, p27^Kip1 and p53 were significantly up-regulated after dihydrofolate reductase knockdown. Furthermore, supplementation of 5-methyltetrahydrofolate to the dihydrofolate reductase knockdown cells could weaken the inhibitory effect of dihydrofolate reductase knockdown on cell proliferation, simultaneously, inducing the expression of p53 and p21^waf/cip1 falling back moderately. Our findings suggest that attenuating dihydrofolate reductase may cause imbalanced expression of cell cycle regulators, especially up-regulation of p53-p21^waf/cip1 pathway, leading to G1 cell cycle arrest, thereby inhibiting the growth of endothelial EA.hy926 cells.

収録刊行物

• Ｊｏｕｒｎａｌ　ｏｆ　Ｃｌｉｎｉｃａｌ　Ｂｉｏｃｈｅｍｉｓｔｒｙ　ａｎｄ　Ｎｕｔｒｉｔｉｏｎ

  Ｊｏｕｒｎａｌ　ｏｆ　Ｃｌｉｎｉｃａｌ　Ｂｉｏｃｈｅｍｉｓｔｒｙ　ａｎｄ　Ｎｕｔｒｉｔｉｏｎ 58 (2), 105-113, 2016

  一般社団法人　日本酸化ストレス学会

キーワード

• dihydrofolate reductase
• endothelial cell
• G1 cell cycle
• p21^waf/cip1
• p53

詳細情報

• CRID: 1390001204671996928
• NII論文ID: 130005132515
• DOI: 10.3164/jcbn.15-64
• ISSN: 18805086
• ISSN: 09120009
• Web Site: https://www.jstage.jst.go.jp/article/jcbn/58/2/58_15-64/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2016329669
• 本文言語コード: en
• データソース種別:
  • JaLC
  • Crossref
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可