Abstract 297: Effects of p53 Stabilization During Heart Failure Progression on Telomere Repeat Binding Factor 2 and Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α in the SHHF Rat
The tumor suppressor protein p53 is a cellular stress sensor and transcription factor classically accepted to target the transcription of genes that induce senescence and apoptosis. Diverse stressors including genomic or telomeric DNA damage, telomere uncapping, hypoxia, oxidative stress, and mechanical stress increase stable cellular p53. In models of heart failure and in human failing hearts, p53 is increased. High p53 has also been suggested to be necessary for the transition from hypertrophy to heart failure.
In recent years it has become clear that senescence and apoptosis may not be the only significant deleterious effects of increased cellular p53. It has been suggested that p53 can decrease mitobiogenesis and cellular ATP production by direct repression of PGC1-a expression. Additionally, P53 has been shown to stimulate the expression of Siah1, an E3 ubiquitin ligase that mediates degradation of the telomere binding protein TRF2. TRF2 loss is a form of telomere uncapping that, in cell culture models, causes a subsequent DNA damage response including further p53 stabilization. The relative importance of these p53 linked pathways has yet to be explored in the progression of hypertensive heart failure.
Spontaneously Hypertensive Heart Failure rats (SHHF) rats were sacked at four stages during heart failure progression and LV removed for western blot analysis. Compared to young (2-4 month) rats, 14-15 month rats showed significantly increased p53 levels (2.3 fold), normal TRF2 levels, and slightly decreased PGC1-a (.98 fold). Old SHHFs (20-22mo) had p53, TRF2, and PGC1-a levels similar to 14-15 month rats (2.1, 1.09, and.83 fold, respectively). Rats with end stage heart failure showed a significant 4.5 fold increase in p53 expression, with a corresponding decrease in TRF2 (.74 fold, p=.087), and increase in PGC1-a (1.3 fold, nonsignificant).
These data are in agreement with previous suggestions that increased p53 is most important during the transition from hypertrophy to heart failure, and suggest that levels of p53 encountered in the SHHF model have little effect on PGC1-a and mitobiogenesis, but may mediate an increase in telomere uncapping during heart failure.
- © 2012 by American Heart Association, Inc.