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J. Biol. Chem., Vol. 281, Issue 7, 4339-4347, February 17, 2006

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p53 Mediates the Accelerated Onset of Senescence of Endothelial Progenitor Cells in Diabetes^*

Arturo Rosso, Antonina Balsamo, Roberto Gambino, Patrizia Dentelli, Rita Falcioni, Maurizio Cassader, Luigi Pegoraro, Gianfranco Pagano, and Maria Felice Brizzi¹

From the Department of Internal Medicine, University of Torino, Corso Dogliotti 14, 10126 Torino, Italy and the Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, Via delle Messi d'Oro 156, 00158 Rome, Italy

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.

Received for publication, August 23, 2005 , and in revised form, December 8, 2005.

^* This work was supported by grants from the Italian Association for Cancer Research (to M. F. B. and R. F.), Ministero dell'Università e Ricerca Scientifica, cofinanziamento MURST and fondi ex-60% grants (to M. F. B., M. C., G. P., and L. P.), and by grants from the Ministero della Salute (to R. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 39-011-633-5539; Fax: 39-011-663-7520; E-mail: mariafelice.brizzi{at}unito.it.

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