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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MDPI AG
2021-03-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/9/3/327 |
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| author | Mirjam Schuchardt Jaqueline Herrmann Cornelia Henkel Milen Babic Markus van der Giet Markus Tölle |
| author_facet | Mirjam Schuchardt Jaqueline Herrmann Cornelia Henkel Milen Babic Markus van der Giet Markus Tölle |
| author_sort | Mirjam Schuchardt |
| collection | DOAJ |
| 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<sup>−/−</sup> 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. |
| first_indexed | 2024-03-10T12:59:03Z |
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| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T12:59:03Z |
| publishDate | 2021-03-01 |
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| spelling | doaj.art-75eace354428404cb1176044b6c745052023-11-21T11:40:33ZengMDPI AGBiomedicines2227-90592021-03-019332710.3390/biomedicines9030327Long-Term Treatment of Azathioprine in Rats Induces Vessel MineralizationMirjam Schuchardt0Jaqueline Herrmann1Cornelia Henkel2Milen Babic3Markus van der Giet4Markus Tölle5Department of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin Berlin, 12203 Berlin, GermanyDepartment of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin Berlin, 12203 Berlin, GermanyDepartment of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin Berlin, 12203 Berlin, GermanyDepartment of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin Berlin, 12203 Berlin, GermanyDepartment of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin Berlin, 12203 Berlin, GermanyDepartment of Nephrology and Medical Intensive Care, Charité–Universitätsmedizin Berlin, 12203 Berlin, GermanyMedial 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<sup>−/−</sup> 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.https://www.mdpi.com/2227-9059/9/3/327agingazathioprinecalcificationmineralizationsenescence-associated secretory phenotype |
| spellingShingle | Mirjam Schuchardt Jaqueline Herrmann Cornelia Henkel Milen Babic Markus van der Giet Markus Tölle Long-Term Treatment of Azathioprine in Rats Induces Vessel Mineralization Biomedicines aging azathioprine calcification mineralization senescence-associated secretory phenotype |
| 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 | aging azathioprine calcification mineralization senescence-associated secretory phenotype |
| url | https://www.mdpi.com/2227-9059/9/3/327 |
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