title: Role of NOX2 in mediating doxorubicin-induced senescence in human endothelial progenitor cells.
abstract: Senescence exerts a great impact on both biological and functional properties of circulating endothelial progenitor cells (EPCs), especially in cardiovascular diseases where the physiological process of aging is accelerated upon clinical administration of certain drugs such as doxorubicin. EPC impairment contributes to doxorubicin-induced cardiotoxicity. Doxorubicin accelerates EPC aging, although mechanisms underlying this phenomenon remain to be fully clarified. Here we investigated if Nox2 activity is able to modulate the premature senescence induced in vitro by doxorubicin in human EPCs. Results showed that in conditioned media obtained from late EPC cultures, the levels of interleukin-6, isoprostanes and nitric oxide bioavailability were increased and reduced respectively after 3h of doxorubicin treatment. These derangements returned to physiological levels when cells were co-treated with apocynin or gp91ds-tat (antioxidant and specific Nox2 inhibitors, respectively). Accordingly, Nox2 activity resulted to be activated by doxorubicin. Importantly, we found that Nox2 inhibition reduced doxorubicin-induced EPC senescence, as indicated by a lower percentage of β-gal positive EPCs. In conclusion, Nox2 activity efficiently contributes to the mechanism of oxidative stress-induced increase in premature aging conferred by doxorubicin. The importance of modulation of Nox2 in human EPCs could reveal a useful tool to restore EPC physiological function and properties.
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome polo pontino, C.so della Repubblica 79, 04100 Latina, Italy. Electronic address: elena.defalco@uniroma1.it.
authors.forename: Elena
authors.initials: E
authors.lastname: De Falco
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome polo pontino, C.so della Repubblica 79, 04100 Latina, Italy. Electronic address: roberto.carnevale@uniroma1.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Carnevale
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome polo pontino, C.so della Repubblica 79, 04100 Latina, Italy. Electronic address: francesca.pagano@uniroma1.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pagano
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome polo pontino, C.so della Repubblica 79, 04100 Latina, Italy. Electronic address: isotta.chimenti@uniroma1.it.
authors.forename: Isotta
authors.initials: I
authors.lastname: Chimenti
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome polo pontino, C.so della Repubblica 79, 04100 Latina, Italy. Electronic address: fianchiniluca@hotmail.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Fianchini
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome polo pontino, C.so della Repubblica 79, 04100 Latina, Italy. Electronic address: anto.bordin@libero.it.
authors.forename: Antonella
authors.initials: A
authors.lastname: Bordin
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome polo pontino, C.so della Repubblica 79, 04100 Latina, Italy. Electronic address: camilla.siciliano@uniroma1.it.
authors.forename: Camilla
authors.initials: C
authors.lastname: Siciliano
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome polo pontino, C.so della Repubblica 79, 04100 Latina, Italy. Electronic address: roberto.monticolo@libero.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Monticolo
authors.affiliation: Transfusion Medicine and Immuno-Hematology Unit, Santa Maria Goretti Hospital, Latina, Italy. Electronic address: fequitani@gmail.com.
authors.forename: Francesco
authors.initials: F
authors.lastname: Equitani
authors.affiliation: Department of AngioCardioNeurology, IRCCS NeuroMed, 86077 Pozzilli, IS, Italy. Electronic address: albino.carrizzo@gmail.com.
authors.forename: Albino
authors.initials: A
authors.lastname: Carrizzo
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome polo pontino, C.so della Repubblica 79, 04100 Latina, Italy. Electronic address: mariangela.peruzzi@uniroma1.it.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Peruzzi
authors.affiliation: Department of AngioCardioNeurology, IRCCS NeuroMed, 86077 Pozzilli, IS, Italy. Electronic address: cvecchione@unisa.it.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vecchione
authors.affiliation: Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sant' Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy; Department of AngioCardioNeurology, IRCCS NeuroMed, 86077 Pozzilli, IS, Italy. Electronic address: speranza.rubattu@uniroma1.it.
authors.forename: Speranza
authors.initials: S
authors.lastname: Rubattu
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome polo pontino, C.so della Repubblica 79, 04100 Latina, Italy; Department of AngioCardioNeurology, IRCCS NeuroMed, 86077 Pozzilli, IS, Italy. Electronic address: sebastiano.sciarretta@uniroma1.it.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Sciarretta
authors.affiliation: Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome polo pontino, C.so della Repubblica 79, 04100 Latina, Italy; Department of AngioCardioNeurology, IRCCS NeuroMed, 86077 Pozzilli, IS, Italy. Electronic address: fraticello@inwind.it.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Frati
mesh_terms: D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects*; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D066026:Endothelial Progenitor Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D028421:Isoprostanes / Q000378:metabolism; D000074662:NADPH Oxidase 2 / Q000378:metabolism*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D028421:Isoprostanes; D004317:Doxorubicin; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2
keywords: Aging; Cardiovascular diseases; Doxorubicin; Endothelial progenitor cells; Nox2