Porcine endothelium induces DNA-histone complex formation in human whole blood: a harmful effect of histone on coagulation and endothelial activation.
Neutrophils play a role in xenograft rejection. When neutrophils are stimulated, they eject the DNA-histone complex into the extracellular space, called neutrophil extracellular traps (NET). We investigated whether NET formation actively occurs in the xenograft and contributes to coagulation and endothelial activation.



Human whole blood was incubated with porcine aortic endothelial cells (pEC) from wild-type or α1,3-galactosyltransferase gene-knockout (GTKO) pigs. In the supernatant plasma from human blood, the level of the DNA-histone complex was measured by ELISA, and thrombin generation was measured using a calibrated automated thrombogram. Histone-induced tissue factor and adhesion molecule expression were measured by flow cytometry.



pEC from both wild-type and GTKO pigs significantly induced DNA-histone complex formation in human whole blood. The DNA-histone complex produced shortened the thrombin generation time and clotting time. Histone alone dose-dependently induced tissue factor and adhesion molecule expression in pEC. Aurintricarboxylic acid pretreatment partially inhibited pEC-induced DNA-histone complex formation.



DNA-histone complex actively generated upon xenotransplantation is a novel target to inhibit coagulation and endothelial activation. To prevent tissue factor and adhesion molecule expression, a strategy to block soluble histone may be required in xenotransplantation.
Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.|Xenotransplantation Research Center and Transplantation Research Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Hyun Ju
HJ
Yoo
Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.|Xenotransplantation Research Center and Transplantation Research Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Ji-Eun
JE
Kim
Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.|Xenotransplantation Research Center and Transplantation Research Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Ja Yoon
JY
Gu
Xenotransplantation Research Center and Transplantation Research Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Sae Bom
SB
Lee
Xenotransplantation Research Center and Transplantation Research Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.|Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul, Korea.
Hyun Joo
HJ
Lee
Xenotransplantation Research Center and Transplantation Research Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.|Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul, Korea.
Ho Young
HY
Hwang
Xenotransplantation Research Center and Transplantation Research Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.|Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul, Korea.
Yoohwa
Y
Hwang
Xenotransplantation Research Center and Transplantation Research Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.|Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul, Korea.
Young Tae
YT
Kim
Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea.|Xenotransplantation Research Center and Transplantation Research Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
Hyun Kyung
HK
Kim
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D003167:Complement Activation / Q000502:physiology; D004247:DNA / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D006084:Graft Rejection / Q000517:prevention & control; D064593:Heterografts / Q000276:immunology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D013552:Swine; D013917:Thrombin / Q000494:pharmacology; D013925:Thromboplastin / Q000378:metabolism*; D014183:Transplantation, Heterologous / Q000379:methods
D006657:Histones; D004247:DNA; D013925:Thromboplastin; D013917:Thrombin
DNA-histone complex; endothelial adhesion molecules; neutrophil extracellular traps; thrombin generation; tissue factor; xenotransplantation