Caffeic acid attenuates rat liver injury after transplantation involving PDIA3-dependent regulation of NADPH oxidase

• Published in: Free radical biology & medicine 2018-12, Vol.129, p.202-214
• Main Authors: Mu, Hong-Na, Li, Quan, Fan, Jing-Yu, Pan, Chun-Shui, Liu, Yu-Ying, Yan, Li, Sun, Kai, Hu, Bai-He, Huang, Dan-Dan, Zhao, Xin-Rong, Chang, Xin, Wang, Chuan-She, He, Shu-Ya, He, Ke, Yang, Bao-Xue, Han, Jing-Yan
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - isolation & purification; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; Caffeic Acids - isolation & purification; Caffeic Acids - pharmacology; Cell Hypoxia - genetics; Cell Line; Gene Expression Regulation; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver microcirculatory disturbance; Liver Transplantation; Male; NADPH Oxidases - genetics; NADPH Oxidases - metabolism; Protein Disulfide-Isomerases - antagonists & inhibitors; Protein Disulfide-Isomerases - genetics; Protein Disulfide-Isomerases - metabolism; Protein Subunits - genetics; Protein Subunits - metabolism; Rats; Rats, Sprague-Dawley; Reperfusion Injury - genetics; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Reperfusion Injury - prevention & control; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Salvia miltiorrhiza; Salvia miltiorrhiza - chemistry; Signal Transduction; Superoxide anion; Transplantation, Homologous
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2018.09.009

The transplanted liver inevitably suffers from ischemia reperfusion (I/R) injury, which represents a key issue in clinical transplantation determining early outcome and long-term graft survival. A solution is needed to deal with this insult. This study was undertaken to explore the effect of Caffeic acid (CA), a naturally occurring antioxidant, on I/R injury of grafted liver and the mechanisms involved. Male Sprague–Dawley rats underwent orthotopic liver transplantation (LT) in the absence or presence of CA administration. In vitro, HL7702 cells were subjected to hypoxia/reoxygenation. LT led to apparent hepatic I/R injury, manifested by deteriorated liver function, microcirculatory disturbance and increased apoptosis, along with increased PDIA3 expression and nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase activity, and membrane translocation of NADPH oxidase subunits. Treatment with CA attenuated the above alterations. siRNA/shRNA-mediated knockdown of PDIA3 in HL7702 cells and rats played the same role as CA not only in inhibiting ROS production and NADPH oxidase activity, but also in alleviating hepatocytes injury. CA protects transplanted livers from injury, which is likely attributed to its protection of oxidative damage by interfering in PDIA3-dependent activation of NADPH oxidase. [Display omitted] •Caffeic acid (CA) protected transplanted liver from ischemia and reperfusion injury.•CA attenuated transplanted liver microcirculatory dysfunction.•We found PDIA3 activated NADPH oxidase via a so far unknown pathway.•CA reduced PDIA3-dependent activation of NADPH oxidase.