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1 Department of Medicine, Pharmacology and Pathology, New York Medical College, Valhalla, NY, USA
2 Brander Cancer Institute, New York Medical College, Valhalla, NY, USA
* To whom correspondence should be addressed. E-mail: jun_chen{at}nymc.edu.
We have previously found that non-enzymatically glycated collagen I (GC), mimicking diabetic microenvironment, can induce senescent phenotype in early passage human umbilical vein endothelial cell (HUVEC). In the present study, we explored the functional involvement of cell cycle checkpoint pathways in initiating of GC-induced premature endothelial cell senescence. Compared to native collagen (NC), early passage HUVEC showed increased p53, p21CIP1 (p21) and p16INK4a (p16) mRNA expression after exposure to GC. 24 hours after transfection of p16, p21 and p53-EGFP recombinant plasmids, HUVECs entered G1-phase cell cycle arrest. By day 3 and 5, HUVEC transfected with p16-EGFP showed an increased proportion of senescent cells, and this increase was more prominent in the GFPpositive cell population, which exhibited 68% of senescent cells. Transfection of p21 also induced senescence but only by day 5. Co-transfection of p16 and p21 showed no additive effect. Transfection of p21 or p53 induced apoptosis in HUVEC. Next, we suppressed endogenous p53, p21, p16 or Rb gene expression through siRNA strategy, and investigated their influence in p16- and p21- initiated endothelial cell senescence. Analysis indicated that suppression of p53 expression can abolish senescence induced by p16 overexpression. Paradoxically, this effect was not observed when p21 was suppressed. On the other hand, suppressing of Rb eliminated senescence initiated by either p16 or p21 overexpression. In summary, the p53/p21 pathway is mainly responsible for GC-induced apoptosis, but the coordinated activation of p53/p21 and p16 pathway is responsible for GC-induced endothelial cell senescence through a Rb dependent mechanism.
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