The Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 510000, China.
Department of Laboratory Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, 510120, China.
Biochem Biophys Res Commun. 2023 Jul 30;667:1-9. doi: 10.1016/j.bbrc.2023.04.105. Epub 2023 Apr 28.
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.
心肌缺血/再灌注（I/R）诱导的心脏血管内皮损伤是心脏 I/R 损伤早期出现的重要病理过程。自噬溶酶体途径对于维持细胞内稳态至关重要。然而，在心肌 I/R 损伤中，自噬溶酶体途径的作用存在争议。本研究旨在利用氧葡萄糖剥夺/氧葡萄糖再灌注（OGD/OGR）模拟心肌 I/R 损伤，评估自噬溶酶体途径在 I/R 诱导的内皮损伤中的作用。结果显示，内皮细胞暴露于 OGD/OGR 后存在溶酶体功能障碍和自噬流受损。同时，我们的数据显示组织蛋白酶 D（CTSD）的水平呈时间依赖性下降。CTSD 敲低导致溶酶体功能障碍和自噬流受损。相反，恢复 CTSD 水平可保护 HCAECs 免受 OGD/OGR 诱导的自噬溶酶体功能障碍和细胞损伤。我们的研究结果表明，I/R 诱导的受损自噬流而不是过度的自噬起始介导内皮细胞损伤。维持自噬溶酶体功能对于保护内皮细胞免受 I/R 损伤至关重要，而 CTSD 是关键调节因子。因此，专注于恢复 CTSD 功能的策略可能是心脏再灌注损伤的新型治疗方法。
