Redox-dependent purine degradation triggers postnatal loss of cardiac regeneration potential
Yuichi Saito,
Yuki Sugiura,
Akane Sakaguchi,
Tai Sada,
Chihiro Nishiyama,
Rae Maeda,
Mari Kaneko,
Hiroshi Kiyonari,
Wataru Kimura
Affiliations
Yuichi Saito
Laboratory for Heart Regeneration, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan; Corresponding author.
Yuki Sugiura
Multiomics Platform, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, 606-8501, Japan; Human Biology Microbiome Quantum Research Center (WPI-Bio2Q), Keio University School of Medicine, Tokyo, Japan
Akane Sakaguchi
Laboratory for Heart Regeneration, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan
Tai Sada
Laboratory for Heart Regeneration, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan
Chihiro Nishiyama
Laboratory for Heart Regeneration, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan
Rae Maeda
Multiomics Platform, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto, 606-8501, Japan
Mari Kaneko
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, 650-0047, Japan
Hiroshi Kiyonari
Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, 650-0047, Japan
Wataru Kimura
Laboratory for Heart Regeneration, RIKEN Center for Biosystems Dynamics Research, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo, 650-0047, Japan; Corresponding author.
Postnatal cardiomyocyte cell cycle withdrawal is a critical step wherein the mammalian heart loses regenerative potential after birth. Here, we conducted interspecies multi-omic comparisons between the mouse heart and that of the opossum, which have different postnatal time-windows for cardiomyocyte cell cycle withdrawal. Xanthine metabolism was activated in both postnatal hearts in parallel with cardiomyocyte cell cycle arrest. The pentose phosphate pathway (PPP) which produces NADPH was found to decrease simultaneously. Postnatal myocardial tissues became oxidized accordingly, and administration of antioxidants to neonatal mice altered the PPP and suppressed the postnatal activation of cardiac xanthine metabolism. These results suggest a redox-driven postnatal switch from purine synthesis to degradation in the heart. Importantly, inhibition of xanthine metabolism in the postnatal heart extended postnatal duration of cardiomyocyte proliferation and maintained postnatal heart regeneration potential in mice. These findings highlight a novel role of xanthine metabolism as a redox-dependent metabolic regulator of cardiac regeneration potential.
