Cyclophilin D as a potential therapeutic target of liver ischemia/reperfusion injury by mediating crosstalk between apoptosis and autophagy

• Published in: Chronic diseases and translational medicine 2023-09, Vol.9 (3), p.238-249
• Main Authors: Yang, Mengjiao, Wang, Zhihui, Xie, Jin, Reyad‐ul‐Ferdous, Md, Li, Siying, Song, Yongfeng
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Antibodies; Apoptosis; Autophagy; Cell death; cyclophilin D; Hemorrhagic shock; Hepatectomy; Ischemia; ischemia/reperfusion; Laboratory animals; Liver; Microscopy; necrosis; Original; Permeability; Reactive oxygen species; Surgery
• ISSN: 2589-0514; 2095-882X; 2589-0514
• DOI: 10.1002/cdt3.78

Background Liver ischemia/reperfusion (I/R) injury is a complex and multifactorial pathophysiological process. It is well recognized that the membrane permeability transition pore (mPTP) opening of mitochondria plays a crucial role in cell death after I/R injury. Cyclophilin D (CypD) is a critical positive regulator of mPTP. However, the effect of CypD on the pathogenesis of liver I/R injury and whether CypD is a potential therapeutic target are still unclear. Methods We constructed liver‐specific CypD knockout and AAV8‐peptidyl prolyl isomerase F (PPIF) overexpression mice. Then, a 70% liver I/R injury model was established in mice, with 90 min of ischemia and 6 h of reperfusion. The liver function was detected by the level of serum glutamic pyruvic transaminase (alanine transaminase) and glutamic oxaloacetic transaminase (aspartate aminotransferase), the liver damage score and degree of necrosis were measured by hematoxylin and eosin (H&E) staining of liver tissues. Reactive oxygen species (ROS) staining, apoptosis, and autophagy‐related molecules were used to detect apoptosis and autophagy during liver I/R. Results The liver‐specific knockout of CypD alleviated necrosis and dysfunction in liver I/R injury, by reducing the excessive production of ROS, and inhibiting cell apoptosis and autophagy. On the contrary, overexpression of CypD exacerbated I/R‐induced liver damage. Conclusion We found that the downregulation of CypD expression alleviated liver I/R injury by reducing apoptosis and autophagy through caspase‐3/Beclin1 crosstalk; in contrast, the upregulation of CypD expression aggravated liver I/R injury. Therefore, interfering with the expression of CypD seems to be a promising treatment for liver I/R injury. In this study, we first reported the effect of cyclophilin D (CypD) in liver ischemia/reperfusion (I/R) by establishing liver‐specific CypD knockout and AAV8‐peptidyl prolyl isomerase F overexpression models in vivo. And found the hepatic CypD knockout can alleviate the liver injury caused by I/R by reducing hepatocyte necrosis and apoptosis, and inhibiting the overactivation of autophagy, and vice versa. Key points A liver‐specific cyclophilin D (CypD) knockout mouse model was established, and we first reported the effect of liver‐specific CypD knockout on liver ischemia/reperfusion in mice. This study adds AAV8‐peptidyl prolyl isomerase F overexpression models.