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<p>Myocardial ischemia/reperfusion (I/R) injury undermines the clinical benefit of percutaneous coronary intervention, with cardiac macrophages playing critical roles. Here, using spatial transcriptomics and flow cytometry, we identified adenylyl cyclase 7 (ADCY7) as a macrophage-specific regulator and potential therapeutic target in myocardial I/R injury, and validated its expression in patient samples. By establishing a macrophage depletion/reconstitution model, we demonstrate that macrophage <i>Adcy7</i> deficiency significantly exacerbates myocardial I/R injury and cardiac dysfunction in male mice, whereas <i>Adcy7</i> overexpression attenuates these effects. Macrophage <i>Adcy7</i> deficiency also increases leukocyte infiltration and pro-inflammatory cytokine production. Mechanistically, transcriptomic and phosphoproteomic analyses reveal that ADCY7 activates cAMP-protein kinase A signaling, thereby inhibiting nuclear translocation of NF-κB and restraining the pro-inflammatory response. Combined with the macrophage depletion/reconstitution approach, we developed a photoactivated adenylyl cyclase system that alleviated cardiac inflammation and I/R injury. Our study identifies ADCY7 as a macrophage-intrinsic anti-inflammatory regulator and a promising therapeutic target for myocardial I/R injury.</p>

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Macrophage adenylyl cyclase 7 protects against myocardial ischemia/reperfusion injury in male mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月27日

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  • Guofang Xia,
  • Simeng Zhu,
  • Yujia Liu,
  • Yifan Shi,
  • Jiaxin Chen,
  • Jingwei Pan,
  • Zhong Chen,
  • Peng Wei,
  • Chengxing Shen,
  • Ailian Du,
  • Congfeng Xu

摘要

Myocardial ischemia/reperfusion (I/R) injury undermines the clinical benefit of percutaneous coronary intervention, with cardiac macrophages playing critical roles. Here, using spatial transcriptomics and flow cytometry, we identified adenylyl cyclase 7 (ADCY7) as a macrophage-specific regulator and potential therapeutic target in myocardial I/R injury, and validated its expression in patient samples. By establishing a macrophage depletion/reconstitution model, we demonstrate that macrophage Adcy7 deficiency significantly exacerbates myocardial I/R injury and cardiac dysfunction in male mice, whereas Adcy7 overexpression attenuates these effects. Macrophage Adcy7 deficiency also increases leukocyte infiltration and pro-inflammatory cytokine production. Mechanistically, transcriptomic and phosphoproteomic analyses reveal that ADCY7 activates cAMP-protein kinase A signaling, thereby inhibiting nuclear translocation of NF-κB and restraining the pro-inflammatory response. Combined with the macrophage depletion/reconstitution approach, we developed a photoactivated adenylyl cyclase system that alleviated cardiac inflammation and I/R injury. Our study identifies ADCY7 as a macrophage-intrinsic anti-inflammatory regulator and a promising therapeutic target for myocardial I/R injury.