Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling
EntityUAM. Departamento de Medicina
PublisherNature Publishing Group
10.1038/srep27915Scientific Reports 6 (2016): 27915
ISSN2045-2322 (print); 2045-2322 (online)
Funded byThis 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)
ProjectComunidad de Madrid. S2010/BMD-2378/CIFRA
SubjectsCalcineurin inhibitors; Cyclosporine; Vascular toxicity; Inflammation; Endothelial activation; Medicina
Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.
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
Google Scholar:Rodrigues Díez, Raquel - González-Guerrero, Cristian - Ocaña-Salceda, Carlos - Rodrigues Díez, Raúl - Egido, Jesús - Ortiz, Alberto - Ruiz-Ortega, Marta - Ramos, Adrián M. - Instituto de Investigación Sanitaria Fundación Jiménez Díaz (ISS-FJD)
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