title: Repressor and activator protein accelerates hepatic ischemia reperfusion injury by promoting neutrophil inflammatory response.
abstract: Repressor and activator protein (Rap1) directly regulates nuclear factor-κB (NF-κB) dependent signaling, which contributes to hepatic IRI. We here intended to investigate the effect of Rap1 in hepatic ischemia reperfusion injury (IRI) and to explore the underlying mechanisms. The association of Rap1 expression with hepatic inflammatory response were investigated in both human and rat liver transplantation. The effect of Rap1 in hepatic IRI was studied in Rap1 knockout mice IRI model in vivo and primary cells in vitro. Our results showed that over expression of Rap1 was associated with severe liver graft inflammatory response, especially in living donor liver transplantation. The results were also validated in rat liver transplantation model. In mice hepatic IRI model, the knockout of Rap1 reduced hepatic damage and hepatic inflammatory response. In primary cells, the knockout of Rap1 suppressed neutrophils migration activity and adhesion in response to liver sinusoidal endothelial cells through down-regulating neutrophils F-Actin expression and CXCL2/CXCR2 pathway. In addition, the knockout of Rap1 also decreased production of pro-inflammatory cytokines/chemokines in primary neutrophils and neutrophils-induced hepatocyte damage. In conclusion, Rap1 may induce hepatic IRI through promoting neutrophils inflammatory response. Rap1 may be the potential therapeutic target of attenuating hepatic IRI.
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
authors.forename: Chang Xian
authors.initials: CX
authors.lastname: Li
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
authors.forename: Chung Mau
authors.initials: CM
authors.lastname: Lo
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Qizhou
authors.initials: Q
authors.lastname: Lian
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
authors.forename: Kevin Tak-Pan
authors.initials: KT
authors.lastname: Ng
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
authors.forename: Xiao Bing
authors.initials: XB
authors.lastname: Liu
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
authors.forename: Yuen Yuen
authors.initials: YY
authors.lastname: Ma
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Qi
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
authors.forename: Oscar Wai Ho
authors.initials: OW
authors.lastname: Yeung
authors.affiliation: Institute of Molecular and Cellular Biology, Biopolis, Singapore.
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.
authors.forename: Xin Xiang
authors.initials: XX
authors.lastname: Yang
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
mesh_terms: D000199:Actins / Q000378:metabolism; D064591:Allografts / Q000473:pathology; D000818:Animals; D001706:Biopsy; D001854:Bone Marrow Cells / Q000378:metabolism; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D054426:Chemokine CXCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D016031:Liver Transplantation / Q000009:adverse effects; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism*; D061251:Primary Cell Culture; D051381:Rats; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism*; D000089804:Shelterin Complex; D015398:Signal Transduction; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D054426:Chemokine CXCL2; D016328:NF-kappa B; D023063:Receptors, Interleukin-8B; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; C548558:TERF2IP protein, mouse; D034501:Telomere-Binding Proteins
keywords: hepatic ischemia reperfusion injury; inflammatory response; liver transplantation; neutrophils migration; nuclear factor-κB