Rap1A accelerates homocysteine-induced ANA-1 cells inflammation via synergy of FoxO1 and DNMT3a

Cell Signal. 2023 Jun:106:110627. doi: 10.1016/j.cellsig.2023.110627. Epub 2023 Feb 14.

Abstract

Abnormal elevation of homocysteine (Hcy) level accelerates atherosclerosis through promote macrophage inflammation, while the precise mechanisms remain to be well elucidated. Previous study revealed that Rap1A is involved in the development of atherosclerosis, but little is known regarding the regulation of macrophage inflammation induced by Hcy and its potential mechanisms. In the present study, we demonstrated that Hcy upregulates Rap1A expression and knockdown of Rap1A inhibited pro-inflammatory cytokines IL-6 and TNF-α levels in ANA-1 cells. Mechanistically, DNMT3a-mediated DNA hypomethylation of Rap1A promoter accelerates Hcy-induced ANA-1 cells inflammation. Furthermore, FoxO1 transcriptionally activate Rap1A by direct binding to its promoter. More importantly, Hcy could enhance FoxO1 interaction with DNMT3a and synergistically promote the expression of Rap1A resulting in accelerate ANA-1 cells inflammation. These data indicate that Rap1A is a novel and important regulator in Hcy-induced ANA-1 cells inflammation.

Keywords: DNA methylation; FoxO1; Homocysteine; Inflammation; Rap1A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atherosclerosis* / metabolism
  • Cells, Cultured
  • DNA Methylation
  • Forkhead Box Protein O1 / metabolism
  • Homocysteine* / pharmacology
  • Inflammation / genetics
  • Mice
  • rap1 GTP-Binding Proteins / genetics
  • rap1 GTP-Binding Proteins / metabolism

Substances

  • Forkhead Box Protein O1
  • Homocysteine
  • rap1 GTP-Binding Proteins
  • rap1A protein, mouse
  • Foxo1 protein, mouse
  • Dnmt3a protein, mouse