p53 Mediates the accelerated onset of senescence of endothelial progenitor cells in diabetes.
Adverse metabolic factors, including oxidized small and dense low density lipoprotein (ox-dmLDL) can contribute to the reduced number and the impaired functions of circulating endothelial progenitors (EPC) in diabetic patients. To elucidate the molecular mechanisms involved, EPC from normal donors were cultured in the presence of ox-dmLDL. Under these experimental conditions EPC undergo to senescent-like growth arrest. This effect is associated with Akt activation, p21 expression, p53 accumulation, and retinoblastoma protein dephosphorylation and with a reduced protective effect against oxidative damage. Moreover, depletion of endogenous p53 expression by small interfering RNA demonstrates that the integrity of this pathway is essential for senescence to occur. Activation of the Akt/p53/p21 signaling pathway and accelerated onset of senescence are also detectable in EPC from diabetic patients. Finally, diabetic EPC depleted of endogenous p53 do not undergo to senescence-growth arrest and acquire the ability to form tube-like structures in vitro. These observations identify the activation of the p53 signaling pathway as a crucial event that can contribute to the impaired neovascularization in diabetes.
Rosso
Arturo
A
Department of Internal Medicine, University of Torino, Italy.
Balsamo
Antonina
A
Gambino
Roberto
R
Dentelli
Patrizia
P
Falcioni
Rita
R
Cassader
Maurizio
M
Pegoraro
Luigi
L
Pagano
Gianfranco
G
Brizzi
Maria Felice
MF
D000328:Adult; D018952:Antigens, CD34 / Q000032:analysis; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D003920:Diabetes Mellitus / Q000473:pathology*; D042783:Endothelial Cells / Q000166:cytology*; D005260:Female; D006031:Glycosylation; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000633:toxicity; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D018952:Antigens, CD34; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008077:Lipoproteins, LDL; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C099252:oxidized low density lipoprotein; D051057:Proto-Oncogene Proteins c-akt