Forkhead box P1 transcriptionally activates IGF-1 to lighten ox-LDL-induced endothelial cellular senescence by inactivating NLRP3 inflammasome

Biogerontology. 2024 Nov 25;26(1):15. doi: 10.1007/s10522-024-10151-5.

Abstract

Endothelial cell (EC) senescence is a major contributor in atherosclerosis (AS) development. Herein, the role of forkhead box P transcription factor 1 (FOXP1) and insulin-like growth factor (IGF)-1 in regulating EC senescence during AS progression was investigated. The mRNA and protein expressions were assessed using qRT-PCR and western blot. IL-1β and IL-18 secretion levels were analyzed by ELISA. Cell viability and pyroptosis were determined by MTT assay and flow cytometry, respectively. SA β-Gal staining was used to measure cell senescence. Tube formation assay was adopted to detect the angiogenesis ability. Dual-luciferase reporter and ChIP assays were used to investigate the relationship between FOXP1 and IGF‑1. ox-LDL stimulation significantly reduced FOXP1 and IGF-1 expression levels in human aortic endothelial cells (HAECs). FOXP1 or IGF-1 overexpression both mitigated ox-LDL-induced cellular senescence and NLRP3 activation in HAECs. It was subsequently revealed that FOXB1 transcriptionally activated IGF-1 expression in HAECs by binding to IGF-1 promoter. Rescue experiments demonstrated that IGF-1 silencing abolished the inhibitory impact of FOXP1 overexpression on ox-LDL-induced cellular senescence and NLRP3 activation in HAECs. FOXP1 transcriptionally activated IGF-1 to lighten ox-LDL-induced endothelial cellular senescence by inactivating NLRP3 inflammasome.

Keywords: Atherosclerosis; Endothelial cell senescence; FOXP1; IGF-1; NLRP3 inflammasome.

MeSH terms

  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Cells, Cultured
  • Cellular Senescence*
  • Endothelial Cells* / metabolism
  • Forkhead Transcription Factors* / genetics
  • Forkhead Transcription Factors* / metabolism
  • Humans
  • Inflammasomes* / metabolism
  • Insulin-Like Growth Factor I* / metabolism
  • Lipoproteins, LDL* / metabolism
  • Lipoproteins, LDL* / pharmacology
  • NLR Family, Pyrin Domain-Containing 3 Protein* / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism

Substances

  • Forkhead Transcription Factors
  • oxidized low density lipoprotein
  • Lipoproteins, LDL
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Insulin-Like Growth Factor I
  • IGF1 protein, human
  • NLRP3 protein, human
  • FOXP1 protein, human
  • Repressor Proteins