Notch signaling regulates the lifespan of vascular endothelial cells via a p16-dependent pathway

PLoS One. 2014 Jun 20;9(6):e100359. doi: 10.1371/journal.pone.0100359. eCollection 2014.

Abstract

Evolutionarily conserved Notch signaling controls cell fate determination and differentiation during development, and is also essential for neovascularization in adults. Although recent studies suggest that the Notch pathway is associated with age-related conditions, it remains unclear whether Notch signaling is involved in vascular aging. Here we show that Notch signaling has a crucial role in endothelial cell senescence. Inhibition of Notch signaling in human endothelial cells induced premature senescence via a p16-dependent pathway. Conversely, over-expression of Notch1 or Jagged1 prolonged the replicative lifespan of endothelial cells. Notch1 positively regulated the expression of inhibitor of DNA binding 1 (Id1) and MAP kinase phosphatase 1 (MKP1), while MKP1 further up-regulated Id1 expression by inhibiting p38MAPK-induced protein degradation. Over-expression of Id1 down-regulated p16 expression, thereby inhibiting premature senescence of Notch1-deleted endothelial cells. These findings indicate that Notch1 signaling has a role in the regulation of endothelial cell senescence via a p16-dependent pathway and suggest that activation of Notch1 could be a new therapeutic target for treating age-associated vascular diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Binding Proteins / genetics
  • Cellular Senescence* / drug effects
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism*
  • Dual Specificity Phosphatase 1 / metabolism
  • Human Umbilical Vein Endothelial Cells / cytology*
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Humans
  • Inhibitor of Differentiation Protein 1 / metabolism
  • Intercellular Signaling Peptides and Proteins / genetics
  • Jagged-1 Protein
  • Membrane Proteins / genetics
  • Mice
  • Phenotype
  • Protein Kinase Inhibitors / pharmacology
  • Proteolysis / drug effects
  • Receptor, Notch1 / metabolism*
  • Serrate-Jagged Proteins
  • Signal Transduction* / drug effects
  • Up-Regulation / drug effects
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors

Substances

  • Calcium-Binding Proteins
  • Cyclin-Dependent Kinase Inhibitor p16
  • ID1 protein, human
  • Inhibitor of Differentiation Protein 1
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Membrane Proteins
  • Protein Kinase Inhibitors
  • Receptor, Notch1
  • Serrate-Jagged Proteins
  • p38 Mitogen-Activated Protein Kinases
  • Dual Specificity Phosphatase 1

Grants and funding

This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant numbers 2430195, 25126706, 25670382), and the grants from the Ono Medical Research Foundation, the Uehara Memorial Foundation, the NOVARTIS Foundation for the Promotion Science, the Japan Diabetes Foundation, the SENSHIN Medical Research Foundation, the Takeda Science Foundation, and the Mitsubishi Pharma Research Foundation, the Takeda Medical Research Foundation, the SUZUKEN Memorial Foundation (to TM), and the Japan Heart Foundation & Astellas/Pfizer Grant for Research on Atherosclerosis Update and the Japan Heart Foundation Dr. Hiroshi Irisawa & Dr. Aya Irisawa Memorial Research Grant (to YY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.