title: p38 MAPK and JNK antagonistically control senescence and cytoplasmic p16INK4A expression in doxorubicin-treated endothelial progenitor cells.
abstract: Patients treated with low-dose anthracyclines often show late onset cardiotoxicity. Recent studies suggest that this form of cardiotoxicity is the result of a progenitor cell disease. In this study we demonstrate that Cord Blood Endothelial Progenitor Cells (EPCs) exposed to low, sub-apoptotic doses of doxorubicin show a senescence phenotype characterized by increased SA-b-gal activity, decreased TRF2 and chromosomal abnormalities, enlarged cell shape, and disarrangement of F-actin stress fibers accompanied by impaired migratory ability. P16( INK4A) localizes in the cytoplasm of doxorubicin-induced senescent EPCs and not in the nucleus as is the case in EPCs rendered senescent by different stimuli. This localization together with the presence of an arrest in G2, and not at the G1 phase boundary, which is what usually occurs in response to the cell cycle regulatory activity of p16(INK4A), suggests that doxorubicin-induced p16( INK4A) does not regulate the cell cycle, even though its increase is closely associated with senescence. The effects of doxorubicin are the result of the activation of MAPKs p38 and JNK which act antagonistically. JNK attenuates the senescence, p16( INK4A) expression and cytoskeleton remodeling that are induced by activated p38. We also found that conditioned medium from doxorubicin-induced senescent cardiomyocytes does not attract untreated EPCs, unlike conditioned medium from apoptotic cardiomyocytes which has a strong chemoattractant capacity. In conclusion, this study provides a better understanding of the senescence of doxorubicin-treated EPCs, which may be helpful in preventing and treating late onset cardiotoxicity.
authors.affiliation: Division of Cardiology, Research Center of Cardiovascular Biology, University of Genova, Genova, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Spallarossa
authors.forename: Paola
authors.initials: P
authors.lastname: Altieri
authors.forename: Chiara
authors.initials: C
authors.lastname: Barisione
authors.forename: Mario
authors.initials: M
authors.lastname: Passalacqua
authors.forename: Concetta
authors.initials: C
authors.lastname: Aloi
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Fugazza
authors.forename: Francesco
authors.initials: F
authors.lastname: Frassoni
authors.forename: Marina
authors.initials: M
authors.lastname: Podestà
authors.forename: Marco
authors.initials: M
authors.lastname: Canepa
authors.forename: Giorgio
authors.initials: G
authors.lastname: Ghigliotti
authors.forename: Claudio
authors.initials: C
authors.lastname: Brunelli
mesh_terms: D000818:Animals; D016922:Cellular Senescence; D017077:Culture Media, Conditioned / Q000494:pharmacology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D003593:Cytoplasm / Q000201:enzymology; D004317:Doxorubicin / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology; D013234:Stem Cells / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4