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

Cardiac ischemia/reperfusion(I/R) induced-cardiac vascular endothelial injury is an important pathological 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...

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Published in:Biochemical and biophysical research communications 2023-07, Vol.667, p.1-9
Main Authors: Zhuang, Qizhen, Zhang, Yang, Zhu, Yanting, He, Lina, Kang, Chunmin, Ke, Peifeng, Lin, Haibiao, Xiong, Yujuan, Huang, Xianzhang
Format: Article
Language:English
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Summary:Cardiac ischemia/reperfusion(I/R) induced-cardiac vascular endothelial injury is an important pathological 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 deprivation/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. •Oxygen-glucose deprivation/oxygen-glucose resupply impaired autophagy degradation.•Oxygen-glucose deprivation/oxygen-glucose resupply caused lysosomal dysfunction.•Autophagic clearance dysfunction was one of the causes of endothelial injury.•CTSD knockdown mimicked these effects on autophagy-lysosomal function.•CTSD restoration protected endothelial cells against autophagy-lysosomal dysfunction.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2023.04.105