Schuchardt Mirjam, Herrmann Jaqueline, Henkel Cornelia, Babic Milen, van der Giet Markus, Tölle Markus
Department of Nephrology and Medical Intensive Care, Charité-Universitätsmedizin Berlin, 12203 Berlin, Germany.
Department of Biochemistry, Chemistry and Pharmacy, Freie Universität Berlin, 14195 Berlin, Germany.
Biomedicines. 2021 Mar 23;9(3):327. doi: 10.3390/biomedicines9030327.
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.
血管中膜钙化（mVC）与心血管疾病密切相关，尤其是在患有慢性肾脏病（CKD）的患者中。即使在肾移植成功后，心血管死亡率仍然居高不下。有证据表明免疫抑制药物可能会影响血管壁的病理生理机制。此前，我们在体外实验中发现，用硫唑嘌呤（AZA）处理血管平滑肌细胞（VSMC）会诱导mVC。在本研究中，这一效应在接受AZA治疗24周的体内大鼠模型中得到了证实。AZA处理后主动脉组织中的钙含量增加。其病理生理机制包括AZA通过黄嘌呤氧化酶（XO）分解代谢为6-硫尿嘧啶，随后诱导氧化应激。促炎细胞因子，如白细胞介素（IL）-1β和IL-6，在AZA治疗后全身和主动脉组织中均增加。此外，VSMC中核心结合因子α-1、碱性磷酸酶和骨桥蛋白的表达增加。由于在体外实验中，AZA对NLRP3主动脉环的作用可能会减弱，因此该信号通路可能至少部分依赖于NLRP3炎性小体。尽管需要人体研究来证实AZA对血管硬化的有害影响，但这些结果进一步证明了AZA治疗会诱导VSMC钙化及其对血管结构的影响。
