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Long-Term Treatment of Azathioprine in Rats Induces Vessel Mineralization
Mirjam Schuchardt1, Jaqueline Herrmann1,2, Cornelia Henkel1
1Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany.
Insights
Azathioprine (AZA) medication can induce medial vascular calcification (mVC) by increasing calcium in aortic tissue. This occurs via oxidative stress and inflammation, potentially involving the NLRP3 inflammasome pathway.
Area of Science:
- Cardiovascular Research
- Nephrology
- Pharmacology
Background:
- Medial vascular calcification (mVC) is linked to cardiovascular disease, particularly in chronic kidney disease (CKD) patients.
- Increased cardiovascular mortality persists post-kidney transplantation, with immunosuppressants like azathioprine (AZA) suspected to play a role.
Purpose of the Study:
- To investigate the in vivo effects of azathioprine (AZA) on medial vascular calcification (mVC).
- To elucidate the underlying pathophysiological mechanisms of AZA-induced vascular calcification.
Main Methods:
- An in vivo rat model was treated with AZA for 24 weeks.
- Calcium content in aortic tissue was measured.
- Systemic and aortic tissue levels of proinflammatory cytokines (IL-1ß, IL-6) were assessed.
- Expression of VSMC calcification markers and NLRP3 inflammasome activation was evaluated.
Main Results:
- AZA treatment significantly increased calcium content in rat aortic tissue.
- AZA induced oxidative stress and elevated proinflammatory cytokines (IL-1ß, IL-6).
- Vascular smooth muscle cells (VSMCs) showed increased expression of calcification markers.
- The calcification effect was reduced in NLRP3 knockout aortic rings, suggesting pathway involvement.
Conclusions:
- Azathioprine (AZA) administration in vivo induces medial vascular calcification (mVC) in rats.
- The mechanism involves AZA catabolism, oxidative stress, inflammation, and potentially the NLRP3 inflammasome.
- These findings highlight potential vascular risks associated with AZA treatment, warranting further human studies.
Abstract:
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.
