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Suppression of NF ‐kappa B p65 expression attenuates delayed xenograft rejection
Author(s) -
Shen Zhenya,
Ye Wenxue,
Ten Xiaomei
Publication year - 2013
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.12027
Subject(s) - rna , downregulation and upregulation , nfkb1 , transplantation , gene expression , chemistry , microbiology and biotechnology , heart transplantation , in vivo , messenger rna , transfection , cancer research , andrology , medicine , gene , biology , transcription factor , biochemistry
Background Delayed xenograft rejection ( DXR ) involves type II vascular endothelial cell ( VEC ) activation including upregulation of pro‐inflammatory genes, which contributes to infiltration into the graft and a complex process of cytokine production. Approaches to prevent DXR have shown limited success. In this study, we modified heart donors using si RNA in an attempt to attenuate DXR and to improve xenograft survival in the mouse‐to‐rat heterotopic heart transplant model. Methods si RNA technology was used to inhibit NF ‐kappa B p65 gene expression in vivo in mice. After the donor was transfected with si RNA , the effects of NF ‐kappa B si RNA on DXR and expression of NF ‐kappaB and pro‐inflammatory genes were evaluated in a concordant mouse‐to‐rat cardiac xenograft model. Results Treatment of NF ‐kappa B si RNA prolonged median heart graft survival time in the recipient rats from 1.7 days in a PBS control group to 5.4 days in the NF ‐kappa B si RNA‐ treated group (P < 0.05). Compared with normal mouse hearts, the NF ‐kappa B p65 m RNA relative levels following si RNA injection in the donors decreased significantly (approximately 70% reduction) in grafts harvested 12 h after transplantation. The m RNA levels of VCAM ‐1, ICAM ‐1, and interleukin‐1 displayed a similar reduction. Histological evaluation using light and electron microscopy showed that damage of endothelial cells after NF ‐kappa B si RNA treament occured at a later time. Conclusion Transfection of NF ‐kappa B p65 si RNA in donor animals can delay the emergence of DXR . This treatment may be used as part of strategies to minimize the complex and multi‐faceted rejection responses in vascularized xenografts.