Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure

Seitaro Nomura,Takanori Fujita,Haruhiro Toko,Masamichi Ito,Toshiyuki Ko,Kei Ito ,Masahiro Satoh,Kanna Fujita,Eiki Takimoto,Atsuhiko T Naito,Hiroshi Akazawa,Yoshio Kobayashi,Hiroyuki Morita,Tomokazu Sumida,Mutsuo Harada,Tomoaki Higo,Hiroyuki Aburatani,Takashige Tobita,Toshihiro Yamaguchi,Issei Komuro

doi:10.1038/s41467-018-06639-7

Seitaro Nomura, Takanori Fujita + Show 18 more

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https://doi.org/10.1038/s41467-018-06639-7

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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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Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive
Our study establishes that cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes, and can be controlled by appropriate interventions
Pressure overload increased the cellular width-tolength ratio in early cardiac hypertrophy, which is a morphological feature of cardiomyocytes of the concentric hypertrophic heart[14] (Fig. 1b)

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Pressure overload induces a transition from cardiac hypertrophy to heart failure, but its underlying mechanisms remain elusive. Sustained overload causes cardiac dysfunction leading to heart failure[3,4,5] During this process, cardiomyocytes activate various signaling cascades initially for adaptive morphological hypertrophy, followed by a transition to the failing phenotype characterized by elongation and contractile force reduction[6]. Single-cardiomyocyte gene expression analyses have revealed an increase in cell-to-cell transcriptional variation in the aging mouse heart[8] and partial activation of genes involved in de-differentiation and the cell cycle[9] These studies have established that cardiomyocyte gene expression underlies cellular phenotypes and determines cardiac function, but it remains elusive what gene programs regulate morphological remodeling and contribute to maintain and disrupt cardiac homeostasis. Our study establishes that cardiomyocyte identity is encoded in transcriptional programs that orchestrate morphological and functional phenotypes, and can be controlled by appropriate interventions

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