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Long-Term Treatment of Azathioprine in Rats Induces Vessel Mineralization

Medial vascular calcification (mVC) is closely related to cardiovascular disease, especially in patients suffering from chronic kidney disease (CKD). Even after successful kidney transplantation, cardiovascular mortality remains increased. There is evidence that immunosuppressive drugs might influen...

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Autores principales: Schuchardt, Mirjam, Herrmann, Jaqueline, Henkel, Cornelia, Babic, Milen, van der Giet, Markus, Tölle, Markus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004774/
https://www.ncbi.nlm.nih.gov/pubmed/33806932
http://dx.doi.org/10.3390/biomedicines9030327
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author Schuchardt, Mirjam
Herrmann, Jaqueline
Henkel, Cornelia
Babic, Milen
van der Giet, Markus
Tölle, Markus
author_facet Schuchardt, Mirjam
Herrmann, Jaqueline
Henkel, Cornelia
Babic, Milen
van der Giet, Markus
Tölle, Markus
author_sort Schuchardt, Mirjam
collection PubMed
description Medial vascular calcification (mVC) is closely related to cardiovascular disease, especially in patients suffering from chronic kidney disease (CKD). Even after successful kidney transplantation, cardiovascular mortality remains increased. There is evidence that immunosuppressive drugs might influence pathophysiological mechanisms in the vessel wall. Previously, we have shown in vitro that mVC is induced in vascular smooth muscle cells (VSMCs) upon treatment with azathioprine (AZA). This effect was confirmed in the current study in an in vivo rat model treated with AZA for 24 weeks. The calcium content increased in the aortic tissue upon AZA treatment. The pathophysiologic mechanisms involve AZA catabolism to 6-thiouracil via xanthine oxidase (XO) with subsequent induction of oxidative stress. Proinflammatory cytokines, such as interleukin (IL)-1ß and IL-6, increase upon AZA treatment, both systemically and in the aortic tissue. Further, VSMCs show an increased expression of core-binding factor α-1, alkaline phosphatase and osteopontin. As the AZA effect could be decreased in NLRP3(−/−) aortic rings in an ex vivo experiment, the signaling pathway might be, at least in part, dependent on the NLRP3 inflammasome. Although human studies are necessary to confirm the harmful effects of AZA on vascular stiffening, these results provide further evidence of induction of VSMC calcification under AZA treatment and its effects on vessel structure.
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spelling pubmed-80047742021-03-29 Long-Term Treatment of Azathioprine in Rats Induces Vessel Mineralization Schuchardt, Mirjam Herrmann, Jaqueline Henkel, Cornelia Babic, Milen van der Giet, Markus Tölle, Markus Biomedicines Article Medial vascular calcification (mVC) is closely related to cardiovascular disease, especially in patients suffering from chronic kidney disease (CKD). Even after successful kidney transplantation, cardiovascular mortality remains increased. There is evidence that immunosuppressive drugs might influence pathophysiological mechanisms in the vessel wall. Previously, we have shown in vitro that mVC is induced in vascular smooth muscle cells (VSMCs) upon treatment with azathioprine (AZA). This effect was confirmed in the current study in an in vivo rat model treated with AZA for 24 weeks. The calcium content increased in the aortic tissue upon AZA treatment. The pathophysiologic mechanisms involve AZA catabolism to 6-thiouracil via xanthine oxidase (XO) with subsequent induction of oxidative stress. Proinflammatory cytokines, such as interleukin (IL)-1ß and IL-6, increase upon AZA treatment, both systemically and in the aortic tissue. Further, VSMCs show an increased expression of core-binding factor α-1, alkaline phosphatase and osteopontin. As the AZA effect could be decreased in NLRP3(−/−) aortic rings in an ex vivo experiment, the signaling pathway might be, at least in part, dependent on the NLRP3 inflammasome. Although human studies are necessary to confirm the harmful effects of AZA on vascular stiffening, these results provide further evidence of induction of VSMC calcification under AZA treatment and its effects on vessel structure. MDPI 2021-03-23 /pmc/articles/PMC8004774/ /pubmed/33806932 http://dx.doi.org/10.3390/biomedicines9030327 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Schuchardt, Mirjam
Herrmann, Jaqueline
Henkel, Cornelia
Babic, Milen
van der Giet, Markus
Tölle, Markus
Long-Term Treatment of Azathioprine in Rats Induces Vessel Mineralization
title Long-Term Treatment of Azathioprine in Rats Induces Vessel Mineralization
title_full Long-Term Treatment of Azathioprine in Rats Induces Vessel Mineralization
title_fullStr Long-Term Treatment of Azathioprine in Rats Induces Vessel Mineralization
title_full_unstemmed Long-Term Treatment of Azathioprine in Rats Induces Vessel Mineralization
title_short Long-Term Treatment of Azathioprine in Rats Induces Vessel Mineralization
title_sort long-term treatment of azathioprine in rats induces vessel mineralization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004774/
https://www.ncbi.nlm.nih.gov/pubmed/33806932
http://dx.doi.org/10.3390/biomedicines9030327
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