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<p>This study investigates mechanisms related to endothelial cells in myocardial ischaemia–reperfusion (I/R) injury, focusing on the role of high-mobility group box 1 (HMGB1) protein in these cells. Using a murine model, we observed elevated levels of HMGB1 in both the heart and circulation following I/R, with a portion originating from cardiac vascular endothelial cells and cardiomyocytes. Endothelial cell-specific HMGB1 knockout preserved cardiac function after I/R by reducing infarct size, mitigating myocardial damage, maintaining endothelial cell barrier function, and attenuating inflammatory and oxidative stress responses. Single-cell analysis revealed that HMGB1 endothelial knockout altered cardiac cell composition by decreasing the proportion of endothelial cells with high fatty acid-binding protein 4 expression. Mechanistically, HMGB1 endothelial knockout significantly inhibited the expression of absent in melanoma 2 (AIM2)-associated inflammasome- and pyroptosis-related proteins after I/R, whereas AIM2 overexpression exacerbated myocardial injury, inflammation, and the expression of pyroptosis-related proteins. Our findings demonstrate that the endothelial HMGB1-AIM2 axis worsens I/R injury by regulating endothelial cell pyroptosis, suggesting a novel pathway involved in microcirculatory dysfunction during myocardial I/R injury.</p>

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Endothelial HMGB1-AIM2 axis worsens myocardial ischemia—reperfusion injury by regulating endothelial pyroptosis

  • 期刊论文

  • 发表日期：

    2025年8月14日

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  • Rui Chen,
  • Junying Duan,
  • Ye Zhou,
  • Mengfei Cao,
  • Ye Su,
  • Duzhe Jiang,
  • Aibin Tao,
  • Wei Yuan,
  • Zhiying Dai

摘要

This study investigates mechanisms related to endothelial cells in myocardial ischaemia–reperfusion (I/R) injury, focusing on the role of high-mobility group box 1 (HMGB1) protein in these cells. Using a murine model, we observed elevated levels of HMGB1 in both the heart and circulation following I/R, with a portion originating from cardiac vascular endothelial cells and cardiomyocytes. Endothelial cell-specific HMGB1 knockout preserved cardiac function after I/R by reducing infarct size, mitigating myocardial damage, maintaining endothelial cell barrier function, and attenuating inflammatory and oxidative stress responses. Single-cell analysis revealed that HMGB1 endothelial knockout altered cardiac cell composition by decreasing the proportion of endothelial cells with high fatty acid-binding protein 4 expression. Mechanistically, HMGB1 endothelial knockout significantly inhibited the expression of absent in melanoma 2 (AIM2)-associated inflammasome- and pyroptosis-related proteins after I/R, whereas AIM2 overexpression exacerbated myocardial injury, inflammation, and the expression of pyroptosis-related proteins. Our findings demonstrate that the endothelial HMGB1-AIM2 axis worsens I/R injury by regulating endothelial cell pyroptosis, suggesting a novel pathway involved in microcirculatory dysfunction during myocardial I/R injury.