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- Title
Selective inhibition of cyclooxygenase‐2 protects porcine aortic endothelial cells from human antibody‐mediated complement‐dependent cytotoxicity.
- Authors
Chen, Pengfei; Zhao, Yanli; Gao, Hanchao; Huang, Jiabao; Lu, Ying; Song, Jinqi; Lin, Lizhong; Lin, Zejin; Ou, Chunpei; Sun, Huimin; Li, Yajing; Zeng, Changchun; Cooper, David K. C.; Zhan, Yongqiang; Deng, Xuefeng; Mou, Lisha
- Abstract
Background: Cyclooxygenase‐2 (COX‐2) is an inducible enzyme with catalytic activity for biosynthesis of prostaglandins which are the key mediators of inflammation. COX‐2 is also the therapeutic target for widely used non‐steroidal anti‐inflammatory drugs (NSAIDs). However, the involvement of COX‐2 in xenotransplantation (eg, pig‐to‐non‐human primate) remains poorly recognized. Methods: We investigated the mechanisms that regulate COX‐2 expression and the effects of COX‐2 on porcine aortic endothelial cell (PAEC) viability using in vitro pig‐to‐primate xenotransplantation model and in vivo pig‐to‐mouse cellular transplant model. Regulation of COX‐2 expression was assessed by real‐time quantitative polymerase chain reaction (qPCR) and Western blotting. The effects of inhibition or downregulation of COX‐2 on PAEC viability were assessed by propidium iodide (PI)‐Annexin V staining and Cell Counting Kit‐8 assay. Results: Human serum triggered robust COX‐2 expression in PAECs in a dose‐ and time‐dependent manner. Induction of COX‐2 expression by human serum was partially through activation of both canonical and non‐canonical nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κb) signaling and increasing intracellular calcium. Cytokines like tumor necrosis factor alpha (TNF‐α), interleukin 1 beta (IL‐1β), IL‐17, were able to induce COX‐2 expression. Selective inhibition of COX‐2 by celecoxib dramatically decreased PAEC death in vitro and in vivo as defined by propidium iodide (PI)‐Annexin V staining. Consistently, downregulation of COX‐2 expression by NF‐κb inhibitors or calcium chelator BAPTA decreased human serum‐induced PAEC death as well. Silencing of COX‐2 expression by small interfering RNA (siRNA) protected PAEC viability when transplanted under kidney capsule of C57BL/6 mice. Conclusions: Taken together, our data suggest that COX‐2 is highly induced in PAECs by xenogenic serum and associated with human antibody‐mediated complement‐dependent cytotoxicity. COX‐2 might be a potential therapeutic target to improve xenotransplantation.
- Subjects
ENDOTHELIAL cells; ECULIZUMAB; SMALL interfering RNA; TUMOR necrosis factors; INFLAMMATORY mediators; TALL-1 (Protein); INTRACELLULAR calcium; CELL survival
- Publication
Xenotransplantation, 2019, Vol 26, Issue 6, pN.PAG
- ISSN
0908-665X
- Publication type
Article
- DOI
10.1111/xen.12536