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Porcine endothelium induces DNA–histone complex formation in human whole blood: a harmful effect of histone on coagulation and endothelial activation
Author(s) -
Yoo Hyun Ju,
Kim JiEun,
Gu Ja Yoon,
Lee Sae Bom,
Lee Hyun Joo,
Hwang Ho Young,
Hwang Yoohwa,
Kim Young Tae,
Kim Hyun Kyung
Publication year - 2016
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1111/xen.12264
Subject(s) - histone , xenotransplantation , microbiology and biotechnology , tissue factor , coagulation , chemistry , biology , dna , biochemistry , transplantation , medicine
Background 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. Methods 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. Results 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. Conclusions 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.