title: Notch signaling regulates the lifespan of vascular endothelial cells via a p16-dependent pathway.
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.
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Yohko
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Suda
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Tateno
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Okada
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Moriya
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Yokoyama
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Aika
authors.initials: A
authors.lastname: Nojima
authors.affiliation: Kazusa DNA Research Institute, Kisarazu, Chiba, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Shimizu
authors.affiliation: Department of Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan; PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D051881:Receptor, Notch1 / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D002135:Calcium-Binding Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1