Calcineurin inhibitors augment endothelial-to-mesenchymal transition by enhancing proliferation in association with cytokine-mediated activation

Calcineurin Inhibitors (CNIs) are routinely used for immunosuppression following solid organ transplantation. However, the prolonged use of these agents lead to organ fibrosis which limits their efficacy. CNIs induce TGFβ expression, which is reported to augment endothelial-to-mesenchymal transition...

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Vydáno v:	Biochemical and biophysical research communications Ročník 519; číslo 4; s. 667 - 673
Hlavní autoři:	Woda, Craig B., Bruneau, Sarah, Mak, Anne Linde, Haskova, Zdenka, Liu, Kaifeng, Ghosh, Chandra C., Briscoe, David M.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Inc 19.11.2019
Témata:	actin Animals cadherins Cadherins - metabolism Calcineurin inhibitors Calcineurin Inhibitors - pharmacology Cell Proliferation - drug effects Cells, Cultured CHO Cells Chronic allograft rejection Cricetinae Cricetulus cyclosporine Cyclosporine - pharmacology Endothelial cells Endothelial-to-mesenchymal transition Epithelial-Mesenchymal Transition - drug effects fibrosis Human Umbilical Vein Endothelial Cells - drug effects Human Umbilical Vein Endothelial Cells - metabolism Human Umbilical Vein Endothelial Cells - physiology Humans hypoxia immunosuppression inflammation muscles organ transplantation Signal Transduction - drug effects Tacrolimus - pharmacology Transplantation Tumor necrosis factor Tumor Necrosis Factor-alpha - pharmacology Endothelial-to-mesenchymal transition Transplantation Chronic allograft rejection Tumor necrosis factor Endothelial cells Calcineurin inhibitors
ISSN:	0006-291X, 1090-2104, 1090-2104
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Shrnutí:	Calcineurin Inhibitors (CNIs) are routinely used for immunosuppression following solid organ transplantation. However, the prolonged use of these agents lead to organ fibrosis which limits their efficacy. CNIs induce TGFβ expression, which is reported to augment endothelial-to-mesenchymal transition (EndMT), but their role in this process is not known. In these studies, we find that the CNIs FK506 and cyclosporine (CsA) are potent to increase endothelial cell (EC) proliferation using established in vitro assays (P < 0.05). Furthermore, using phosphokinase arrays, we find that each CNI activates the MAPK and Akt/mTOR signaling pathways, and that pharmacological inhibition of each pathway targets CNI-induced proliferative responses (P < 0.001). EndMT was evaluated by FACS for N-cadherin and CD31 expression and by qPCR for the expression of α-smooth muscle actin, N-cadherin and Snail. We find that CNIs do not directly induce dedifferentiation, while TGFβ and hypoxia induce EndMT in small numbers of EC. In contrast, the treatment of EC with the inflammatory cytokine TNFα was potent to elicit an EndMT response, and its effects were most notably in EC following proliferation/doubling. Taken together, these observations suggest that CNIs elicit proliferative responses, which enhance EndMT in association with local inflammation. The clinical implications of these findings are that anti-proliferative therapeutics have high potential to target the initiation of this EndMT response. •Calcineurin inhibitors stimulate endothelial cell proliferation and angiogenesis.•The inflammatory cytokine TNFα is potent to elicit an EndMT response.•Endothelial cell doubling markedly increases susceptibility to TNFα-induced EndMT.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 CCG and DMB served as co-senior authors
ISSN:	0006-291X 1090-2104 1090-2104
DOI:	10.1016/j.bbrc.2019.09.043