Role of NOX2 in mediating doxorubicin-induced senescence in human endothelial progenitor cells

Elena De Falco, Carnevale Roberto, Francesca Pagano, Isotta Chimenti, Luca Fianchini, Antonella Bordin, Camilla Siciliano, Roberto Monticolo, Francesco Equitani, Albino Carrizzo, Mariangela Peruzzi, Carmine Vecchione, Speranza Rubattu, Sebastiano Sciarretta, Giacomo Frati

Research output: Contribution to journalArticlepeer-review

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 3. h 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.

Original languageEnglish
JournalMechanisms of Ageing and Development
DOIs
Publication statusAccepted/In press - Jan 30 2016

Keywords

  • Aging
  • Cardiovascular diseases
  • Doxorubicin
  • Endothelial progenitor cells
  • Nox2

ASJC Scopus subject areas

  • Ageing
  • Developmental Biology

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