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

Seitaro Nomura, Masahiro Satoh, Takanori Fujita, Tomoaki Higo, Tomokazu Sumida, Toshiyuki Ko, Toshihiro Yamaguchi, Takashige Tobita, Atsuhiko T. Naito, Masamichi Ito, Kanna Fujita, Mutsuo Harada, Haruhiro Toko, Yoshio Kobayashi, Kaoru Ito, Eiki Takimoto, Hiroshi Akazawa, Hiroyuki Morita, Hiroyuki Aburatani () and Issei Komuro ()
Additional contact information
Seitaro Nomura: The University of Tokyo
Masahiro Satoh: The University of Tokyo
Takanori Fujita: The University of Tokyo
Tomoaki Higo: Osaka University Graduate School of Medicine
Tomokazu Sumida: The University of Tokyo
Toshiyuki Ko: The University of Tokyo
Toshihiro Yamaguchi: The University of Tokyo
Takashige Tobita: Tokyo Women’s Medical University
Atsuhiko T. Naito: The University of Tokyo
Masamichi Ito: The University of Tokyo
Kanna Fujita: The University of Tokyo
Mutsuo Harada: The University of Tokyo
Haruhiro Toko: The University of Tokyo
Yoshio Kobayashi: Chiba University Graduate School of Medicine
Kaoru Ito: RIKEN Center for Integrative Medical Sciences
Eiki Takimoto: The University of Tokyo
Hiroshi Akazawa: The University of Tokyo
Hiroyuki Morita: The University of Tokyo
Hiroyuki Aburatani: The University of Tokyo
Issei Komuro: The University of Tokyo

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06639-7

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DOI: 10.1038/s41467-018-06639-7

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