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



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.



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.
Das
Biswajit
B
Department of Molecular Cardiology-NB50, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Young
David
D
Vasanji
Amit
A
Gupta
Sudhiranjan
S
Sarkar
Sagartirtha
S
Sen
Subha
S
D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013318:Stroke Volume; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016277:Ventricular Function, Left
D036341:Intercellular Signaling Peptides and Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C065700:myotrophin