Influence of p53 in the transition of myotrophin-induced cardiac hypertrophy to heart failure.

AIMS: Cardiac-specific overexpression of myotrophin (myo) protein in transgenic (myo-Tg) mice results in hypertrophy at 4 weeks that progresses to heart failure (HF) by 36 weeks. Gene profiling showed that p53 expression increases as hypertrophy worsens to HF, suggesting that p53 may influence myo-induced HF. We aimed to define how the p53 signalling cascade affects the spectrum of cardiac hypertrophy (CH)/HF.

METHODS AND RESULTS: Immunoblot analysis showed that in myo-Tg mice (Mus musculus), upregulation of p53 occurs only when hypertrophy transitions to HF (16 weeks onward). To elucidate the role of p53, a double-Tg mouse line (p53(-/-)/myo(+/+)) was developed by crossing myo-Tg mice with p53-null mice. A significant reduction in cardiac mass with improved cardiac function was observed in p53(-/-)/myo(+/+) mice, suggesting that absence of p53 prevents hypertrophy from turning into HF. Analysis via real-time reverse-transcription PCR revealed changes in transcripts of the p53 pathway in p53(-/-)/myo(+/+) mice. Ingenuity Pathway Analysis indicated that cross-talk among several key nodal molecules (e.g. cyclin-dependent kinase inhibitor 1A, caspase-3, nuclear factor kappa-light-chain enhancer of activated B cells etc.) may play a regulatory role in the transition of CH to HF.

CONCLUSION: Our data provide evidence, for the first time, that the coherence of p53 with myo plays an active role during the transition of CH to HF in a model of HF induced by myo overexpression. Transition from CH to HF can be prevented in the absence of p53 in myo-induced hypertrophy. Therefore, deletion/inhibition of p53 could be a therapeutic strategy to prevent CH from transitioning to HF.