Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling
Entidad
UAM. Departamento de MedicinaEditor
Nature Publishing GroupFecha de edición
2016-06-13Cita
10.1038/srep27915
Scientific Reports 6 (2016): 27915
ISSN
2045-2322 (print); 2045-2322 (online)DOI
10.1038/srep27915Financiado por
This work was supported by grants from the Instituto de Salud Carlos III (Ministerio de Economía Competitividad, Gobierno de España): FEDER funds ISCIII RETIC REDINREN RD12/0021, PI11/02242, PI13/00047, PI14/0041, PI14/00386, PI15/01460; Comunidad de Madrid (CIFRA S2010/BMD-2378); Sociedad Española de Nefrología. Salary support: RR-D: CIFRA; CO-S: Fundación Conchita Rábago de Jiménez Díaz; CG-G and RRR-D: REDINREN; AO: Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM); JE and MRO: Universidad Autónoma de Madrid; AMR: Contrato Miguel Serve (ISCIII)Proyecto
Comunidad de Madrid. S2010/BMD-2378/CIFRAVersión del editor
http://dx.doi.org/10.1038/srep27915Materias
Calcineurin inhibitors; Cyclosporine; Vascular toxicity; Inflammation; Endothelial activation; MedicinaResumen
The introduction of the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus greatly reduced the
rate of allograft rejection, although their chronic use is marred by a range of side effects, among them
vascular toxicity. In transplant patients, it is proved that innate immunity promotes vascular injury
triggered by ischemia-reperfusion damage, atherosclerosis and hypertension. We hypothesized that
activation of the innate immunity and inflammation may contribute to CNI toxicity, therefore we
investigated whether TLR4 mediates toxic responses of CNIs in the vasculature. Cyclosporine and
tacrolimus increased the production of proinflammatory cytokines and endothelial activation markers
in cultured murine endothelial and vascular smooth muscle cells as well as in ex vivo cultures of murine
aortas. CNI-induced proinflammatory events were prevented by pharmacological inhibition of TLR4.
Moreover, CNIs were unable to induce inflammation and endothelial activation in aortas from TLR4−/−
mice. CNI-induced cytokine and adhesion molecules synthesis in endothelial cells occurred even in the
absence of calcineurin, although its expression was required for maximal effect through upregulation
of TLR4 signaling. CNI-induced TLR4 activity increased O2
−/ROS production and NF-κB-regulated
synthesis of proinflammatory factors in cultured as well as aortic endothelial and VSMCs. These data
provide new insight into the mechanisms associated with CNI vascular inflammation
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Google Scholar:Rodrigues Díez, Raquel
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González-Guerrero, Cristian
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Ocaña-Salceda, Carlos
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Rodrigues Díez, Raúl
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Egido, Jesús
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Ortiz Arduán, Alberto
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Ruiz Ortega, Marta
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Ramos, Adrián M.
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Instituto de Investigación Sanitaria Fundación Jiménez Díaz (ISS-FJD)
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