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<p>Heart failure (HF) remains a major clinical challenge with poor prognosis despite extensive research and established treatments. Extracellular ATP and adenosine (Ado), as damage-associated molecular patterns (DAMPs), contribute to HF pathogenesis through pro-inflammatory effects. However, <i>in vivo</i> evidence of ATP/Ado dynamics in failing hearts remains elusive. In this study, we investigated the spatiotemporal dynamics of extracellular Ado in a zebrafish HF model using a genetically encoded heart-specific extracellular Ado sensor (GRAB<sub>Ado</sub>). Terfenadine-induced HF zebrafish showed increased extracellular cardiac Ado, indirectly reflecting elevated extracellular ATP release. These findings demonstrate a strong correlation between extracellular ATP/Ado dynamics and HF progression. Furthermore, pharmacological inhibition of vesicular nucleotide transporter (VNUT), a key regulator of ATP vesicle exocytosis, reduced extracellular ATP/Ado levels and ameliorated cardiac dysfunction in the HF model. Co-treatment with a VNUT inhibitor and purinergic modulators showed additive therapeutic effects. Thus, this study aimed to provide <i>in vivo</i> evidence linking extracellular ATP/Ado signaling to HF pathophysiology and highlight VNUT as a novel therapeutic target for HF. Given the multifactorial nature of HF and the limited success of current anti-inflammatory strategies, targeting purinergic signaling through VNUT inhibition offers a promising approach for managing inflammatory mechanisms in HF.</p>

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In vivo visualization of cardiac extracellular adenosine dynamics and its pharmacological modulation in zebrafish heart failure models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月11日

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  • Phurpa Phurpa,
  • Magdeline E. Carrasco Apolinario,
  • Ryohei Umeda,
  • Shinichiro Kume,
  • Hitoshi Teranishi,
  • Nobuyuki Shimizu,
  • Mengting Shan,
  • Kenshiro Shikano,
  • Tatsuki Kurokawa,
  • Takatoshi Hikida,
  • Toshikatsu Hanada,
  • Yulong Li,
  • Reiko Hanada

摘要

Heart failure (HF) remains a major clinical challenge with poor prognosis despite extensive research and established treatments. Extracellular ATP and adenosine (Ado), as damage-associated molecular patterns (DAMPs), contribute to HF pathogenesis through pro-inflammatory effects. However, in vivo evidence of ATP/Ado dynamics in failing hearts remains elusive. In this study, we investigated the spatiotemporal dynamics of extracellular Ado in a zebrafish HF model using a genetically encoded heart-specific extracellular Ado sensor (GRABAdo). Terfenadine-induced HF zebrafish showed increased extracellular cardiac Ado, indirectly reflecting elevated extracellular ATP release. These findings demonstrate a strong correlation between extracellular ATP/Ado dynamics and HF progression. Furthermore, pharmacological inhibition of vesicular nucleotide transporter (VNUT), a key regulator of ATP vesicle exocytosis, reduced extracellular ATP/Ado levels and ameliorated cardiac dysfunction in the HF model. Co-treatment with a VNUT inhibitor and purinergic modulators showed additive therapeutic effects. Thus, this study aimed to provide in vivo evidence linking extracellular ATP/Ado signaling to HF pathophysiology and highlight VNUT as a novel therapeutic target for HF. Given the multifactorial nature of HF and the limited success of current anti-inflammatory strategies, targeting purinergic signaling through VNUT inhibition offers a promising approach for managing inflammatory mechanisms in HF.