Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure. Issue 1 (December 2018)

• Record Type: Journal Article
• Authors: Nomura, Seitaro; Satoh, Masahiro; Fujita, Takanori; Higo, Tomoaki; Sumida, Tomokazu; Ko, Toshiyuki; Yamaguchi, Toshihiro; Tobita, Takashige; Naito, Atsuhiko; Ito, Masamichi; Fujita, Kanna; Harada, Mutsuo; Toko, Haruhiro; Kobayashi, Yoshio; Ito, Kaoru; Takimoto, Eiki; Akazawa, Hiroshi; Morita, Hiroyuki; Aburatani, Hiroyuki; Komuro, Issei
• Is Part Of: Nature communications. Volume 9:Issue 1(2018)
• Page Start: 1
• Page End: 17
• Publication Date: 2018-12
• Subjects: Biology -- Periodicals; Physical sciences -- Periodicals; 505
• DOI: 10.1038/s41467-018-06639-7
• Languages: English
• ISSNs: 2041-1723

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. The mechanisms underlying the transition from cardiac hypertrophy to heart failure following pressure overload are incompletely understood. Here the authors identify the gene programs encoding the morphological and functional characteristics of cardiomyocytes during the transition from early hypertrophy to heart failure via single-cell transcriptomics, establishing a key role for p53 signalling.