Maintenance of cathepsin D-dependent autophagy-lysosomal function protects against cardiac ischemia/reperfusion injury

作者：Zhuang, Qizhen; Zhang, Yang; Zhu, Yanting; He, Lina; Kang, Chunmin; Ke, Peifeng; Lin, Haibiao; Xiong, Yujuan^*; Huang, Xianzhang^*

来源：Biochemical and Biophysical Research Communications, 2023, 667: 1-9.

DOI：10.1016/j.bbrc.2023.04.105

• Ischemia
• reperfusion injury
• Endothelial cells
• Autophagy
• Lysosome
• Cathepsin D

Cardiac ischemia/reperfusion(I/R) induced-cardiac vascular endothelial injury is an important patho-logical process that appears in the early stage of cardiac I/R injury. The autophagy-lysosomal pathway is essential for the maintenance of cellular homeostasis. However, in cardiac I/R injury, the role of the autophagy-lysosomal pathway is controversial. The present study aimed to use oxygen-glucose depri-vation/oxygen-glucose resupply(OGD/OGR) in human coronary artery endothelial cells(HCAECs) with I/R injury to assess the role of the autophagy-lysosomal pathway in I/R-induced endothelial injury. The results revealed lysosomal dysfunction and impaired autophagic flux in endothelial cells exposed to OGD/OGR. Meanwhile, our data showed that the levels of cathepsin D(CTSD) decreased time-dependently. Knockdown of CTSD caused lysosomal dysfunction and impaired autophagic flux. Conversely, restoration of CTSD levels protected HCAECs against OGD/OGR induced-defects in autophagy-lysosomal function and cellular damage. Our findings indicated that I/R induced-impaired autophagic flux, rather than excessive autophagic initiation, mediates endothelial cells injury. The maintenance of autophagy-lysosomal function is critical to protect endothelial cells against I/R injury, and CTSD is a key regulator. Thus, strategies focused on restoring CTSD function are potentially novel treatments for cardiac reperfusion injury.

• 单位
  广州中医药大学