Cyclosporin a disrupts notch signaling and vascular lumen maintenance

PloS One
Raghav PandeyAllan R Albig

Abstract

Cyclosporin A (CSA) suppresses immune function by blocking the cyclophilin A and calcineurin/NFAT signaling pathways. In addition to immunosuppression, CSA has also been shown to have a wide range of effects in the cardiovascular system including disruption of heart valve development, smooth muscle cell proliferation, and angiogenesis inhibition. Circumstantial evidence has suggested that CSA might control Notch signaling which is also a potent regulator of cardiovascular function. Therefore, the goal of this project was to determine if CSA controls Notch and to dissect the molecular mechanism(s) by which CSA impacts cardiovascular homeostasis. We found that CSA blocked JAG1, but not Dll4 mediated Notch1 NICD cleavage in transfected 293T cells and decreased Notch signaling in zebrafish embryos. CSA suppression of Notch was linked to cyclophilin A but not calcineurin/NFAT inhibition since N-MeVal-4-CsA but not FK506 decreased Notch1 NICD cleavage. To examine the effect of CSA on vascular development and function, double transgenic Fli1-GFP/Gata1-RFP zebrafish embryos were treated with CSA and monitored for vasculogenesis, angiogenesis, and overall cardiovascular function. Vascular patterning was not obviously impacted by CSA tre...Continue Reading

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Citations

Mar 15, 2016·Expert Opinion on Drug Discovery·Ivan Fraietta, Fabio Gasparri
Jun 2, 2017·Journal of Applied Toxicology : JAT·Bonnie L RobinsonJyotshna Kanungo
May 20, 2020·Molecular Therapy. Methods & Clinical Development·Kaytlyn A GerbinCharles E Murry

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Methods Mentioned

BETA
transfection
transgenic
fluorescence microscopy
dissecting

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