Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure.
Seitaro NomuraMasahiro SatohTakanori FujitaTomoaki HigoTomokazu S SumidaToshiyuki KoToshihiro YamaguchiTakashige TobitaAtsuhiko T NaitoMasamichi ItoKanna FujitaMutsuo HaradaHaruhiro TokoYoshio KobayashiKaoru ItoEiki TakimotoHiroshi AkazawaHiroyuki MoritaHiroyuki AburataniIssei KomuroPublished in: Nature communications (2018)
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.
Keyphrases
- genome wide
- heart failure
- angiotensin ii
- high glucose
- oxidative stress
- endothelial cells
- gene expression
- single cell
- dna methylation
- transcription factor
- genome wide identification
- atrial fibrillation
- poor prognosis
- stem cells
- left ventricular
- cell therapy
- rna seq
- mesenchymal stem cells
- long non coding rna
- binding protein