Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis

Toshiyuki Ko, Seitaro Nomura (), Shintaro Yamada, Kanna Fujita, Takanori Fujita, Masahiro Satoh, Chio Oka, Manami Katoh, Masamichi Ito, Mikako Katagiri, Tatsuro Sassa, Bo Zhang, Satoshi Hatsuse, Takanobu Yamada, Mutsuo Harada, Haruhiro Toko, Eisuke Amiya, Masaru Hatano, Osamu Kinoshita, Kan Nawata, Hiroyuki Abe, Tetsuo Ushiku, Minoru Ono, Masashi Ikeuchi, Hiroyuki Morita, Hiroyuki Aburatani () and Issei Komuro ()
Additional contact information
Toshiyuki Ko: The University of Tokyo
Seitaro Nomura: The University of Tokyo
Shintaro Yamada: The University of Tokyo
Kanna Fujita: The University of Tokyo
Takanori Fujita: The University of Tokyo
Masahiro Satoh: The University of Tokyo
Chio Oka: Nara Institute of Science and Technology
Manami Katoh: The University of Tokyo
Masamichi Ito: The University of Tokyo
Mikako Katagiri: The University of Tokyo
Tatsuro Sassa: The University of Tokyo
Bo Zhang: The University of Tokyo
Satoshi Hatsuse: The University of Tokyo
Takanobu Yamada: The University of Tokyo
Mutsuo Harada: The University of Tokyo
Haruhiro Toko: The University of Tokyo
Eisuke Amiya: The University of Tokyo
Masaru Hatano: The University of Tokyo
Osamu Kinoshita: The University of Tokyo
Kan Nawata: St. Marianna University School of Medicine
Hiroyuki Abe: The University of Tokyo
Tetsuo Ushiku: The University of Tokyo
Minoru Ono: The University of Tokyo
Masashi Ikeuchi: Tokyo Medical and Dental University
Hiroyuki Morita: The University of Tokyo
Hiroyuki Aburatani: The University of Tokyo
Issei Komuro: The University of Tokyo

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure.

Date: 2022
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DOI: 10.1038/s41467-022-30630-y

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