title: Klotho attenuated antibody-mediated porcine endothelial cell activation and injury.
abstract: Long-term success in pig-to-primate xenotransplantation is currently hampered by acute vascular rejection (AVR), characterized by endothelial cell (EC) activation and injury. Klotho has anti-apoptotic, anti-inflammatory effects on EC and protects EC against reactive oxygen species, rendering klotho a promising molecule to control AVR. In this study, porcine ECs were pre-incubated with klotho and then exposed to xenoreactive antibodies and complement. Real-time PCR revealed that klotho suppressed antibody-induced pro-inflammatory gene expression of VCAM-1 and IL-1α. NF-κB activation, IκBα phosphorylation, was also attenuated by klotho administration. Furthermore, klotho induced in porcine EC resistance against complement-dependent cytotoxicity. Accompanying this change, the binding of IgG and IgM xenoreactive antibodies to porcine EC was decreased and the expression of anti-inflammatory gene HO-1 was upregulated. These findings indicated that klotho protein protected porcine EC from activation and injury caused by binding of xenoreactive antibodies and was a promising candidate molecule in a multitransgenic pig strategy for xenotransplantation.
authors.affiliation: Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China.|Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China.|Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Hanchao
authors.initials: H
authors.lastname: Gao
authors.affiliation: Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Chungu
authors.initials: C
authors.lastname: Hong
authors.affiliation: Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Chen
authors.initials: C
authors.lastname: He
authors.affiliation: Key Laboratory of Farm Animal Genetic Resource and Germplasm Innovation of Ministry of Agriculture, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Shenzhen, China.
authors.forename: Dengke
authors.initials: D
authors.lastname: Pan
authors.affiliation: Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Xenotransplantation Program/Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Hara
authors.affiliation: Xenotransplantation Program/Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, 35233, USA.
authors.forename: David K C
authors.initials: DK
authors.lastname: Cooper
authors.affiliation: Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Zesong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Shenzhen, China.
authors.forename: Lisha
authors.initials: L
authors.lastname: Mou
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003165:Complement System Proteins / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology*; D004730:Endothelium, Vascular / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism*; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D000090265:Klotho Proteins; D013552:Swine; D014183:Transplantation, Heterologous / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D014409:Tumor Necrosis Factor-alpha; D003165:Complement System Proteins; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: endothelial cell; klotho; xenoreactive antibodies; xenotransplantation