Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-018-06639-7
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Funding
- Japan Foundation for Applied Enzymology
- SENSHIN Medical Research Foundation
- KANAE Foundation for the Promotion of Medical Science
- MSD Life Science Foundation
- Tokyo Biomedical Research Foundation
- Astellas Foundation for Research on Metabolic Disorders
- NOVARTIS Foundation (Japan) for the Promotion of Science
- Japanese Circulation Society
- Practical Research Project for Rare/Intractable Diseases from the Japanese Agency for Medical Research and Development
- AMED-PRIME, AMED [JP18gm6210010]
- AMED-CREST, AMED [JP18bm0804010, JP18gm0810013]
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Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive. Here we reconstruct a trajectory of cardiomyocyte remodeling and clarify distinct cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure, by integrating single-cardiomyocyte transcriptome with cell morphology, epigenomic state and heart function. During early hypertrophy, cardiomyocytes activate mitochondrial translation/metabolism genes, whose expression is correlated with cell size and linked to ERK1/2 and NRF1/2 transcriptional networks. Persistent overload leads to a bifurcation into adaptive and failing cardiomyocytes, and p53 signaling is specifically activated in late hypertrophy. Cardiomyocyte-specific p53 deletion shows that cardiomyocyte remodeling is initiated by p53-independent mitochondrial activation and morphological hypertrophy, followed by p53-dependent mitochondrial inhibition, morphological elongation, and heart failure gene program activation. Human single-cardiomyocyte analysis validates the conservation of the pathogenic transcriptional signatures. Collectively, cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes.
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