Abstract 13388: Accelerated Senescence of Cord Blood Endothelial Progenitor Cells From Premature Neonates is Driven by Sirt1 Decreased Expression
Epidemiological and experimental studies indicate that low birth weight, in particular preterm birth, is considered a major independent risk factor for cardiovascular diseases. Early vascular dysfunction is described in preterm neonates with low birth weight (PT) and is associated with an impairment of angiogenic properties of endothelial colony forming cells (ECFC). Changes in number and function of endothelial progenitor cells have been implicated in cardiovascular diseases. We hypothesized here that ECFC dysfunction from PT might result from premature senescence and investigated the underlying mechanisms.
For that, ECFCs of PT (n=29) or term (n=18) neonates were isolated from cord blood. PT-ECFC displayed an increase of the senescence-associated ß-galactosidase (SA-ß-Gal) activity and a sustained growth arrest, inversely correlated with gestational age. An increased p16 expression together with both reduced p21 and pRB phosphorylation, in the absence of telomere shortening, suggested that stress-induced senescence rather than replicative senescence occurs in PT ECFCs. Together with these findings an increased oxidative stress was found in PT ECFCs. Interestingly, we found that expression of SIRT1, an NAD-dependent deacetylase possessing anti-aging activities, was dramatically decreased at the RNA and protein levels in PT-ECFCs and led to an endothelial senescence state subsequent to epigenetic silencing of its promoter. Not only in vitro, also circulating mononuclear cells presented a reduction in SIRT1 expression. Transient SIRT1 overexpression or chemical-induction after resveratrol treatment led to a significant reduction of SA-ß-Gal staining and senescence in PT-ECFCs, accompanied by increased cell proliferation. Furthermore, resveratrol treatment rescues PT-ECFCs angiogenic defect in a SIRT1-dependent manner and decreased ROS production.
In conclusion, we demonstrated that SIRT1 deficiency drives stress induced senescence of PT-ECFCs, and acts as a critical determinant of endothelial dysfunction. Moreover, our findings lay news grounds for understanding the long-term effect of prematurity on the development of cardiovascular diseases in adults and opened new perspectives for a targeted therapeutic strategy.
- © 2013 by American Heart Association, Inc.