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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Published in:Biochemical and biophysical research communications Vol. 519; no. 4; pp. 667 - 673
Main Authors: Woda, Craig B., Bruneau, Sarah, Mak, Anne Linde, Haskova, Zdenka, Liu, Kaifeng, Ghosh, Chandra C., Briscoe, David M.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 19.11.2019
Subjects:
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
Online Access:Get full text
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Summary: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.
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CCG and DMB served as co-senior authors
ISSN:0006-291X
1090-2104
1090-2104
DOI:10.1016/j.bbrc.2019.09.043