Department of Nephrology, Xuanwu Hospital, Capital Medical University, Changchun Street 45#, 100053, Beijing, China.
National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing, China.
Cell Death Dis. 2022 Mar 30;13(3):283. doi: 10.1038/s41419-022-04735-7.
Irisin protects the cardiovascular system against vascular diseases. However, its role in chronic kidney disease (CKD) -associated vascular calcification (VC) and the underlying mechanisms remain unclear. In the present study, we investigated the potential link among Irisin, pyroptosis, and VC under CKD conditions. During mouse vascular smooth muscle cell (VSMC) calcification induced by β-glycerophosphate (β-GP), the pyroptosis level was increased, as evidenced by the upregulated expression of pyroptosis-related proteins (cleaved CASP1, GSDMD-N, and IL1B) and pyroptotic cell death (increased numbers of PI-positive cells and LDH release). Reducing the pyroptosis levels by a CASP1 inhibitor remarkably decreased calcium deposition in β-GP-treated VSMCs. Further experiments revealed that the pyroptosis pathway was activated by excessive reactive oxygen species (ROS) production and subsequent NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in calcified VSMCs. Importantly, Irisin effectively inhibited β-GP-induced calcium deposition in VSMCs in vitro and in mice aortic rings ex vivo. Overexpression of Nlrp3 attenuated the suppressive effect of Irisin on VSMC calcification. In addition, Irisin could induce autophagy and restore autophagic flux in calcified VSMCs. Adding the autophagy inhibitor 3-methyladenine or chloroquine attenuated the inhibitory effect of Irisin on β-GP-induced ROS production, NLRP3 inflammasome activation, pyroptosis, and calcification in VSMCs. Finally, our in vivo study showed that Irisin treatment promoted autophagy, downregulated ROS level and thereby suppressed pyroptosis and medial calcification in aortic tissues of adenine-induced CKD mice. Together, our findings for the first time demonstrated that Irisin protected against VC via inducing autophagy and inhibiting VSMC pyroptosis in CKD, and Irisin might serve as an effective therapeutic agent for CKD-associated VC.
鸢尾素可保护心血管系统免受血管疾病的侵害。然而，其在慢性肾脏病（CKD）相关血管钙化（VC）中的作用及其潜在机制尚不清楚。在本研究中，我们研究了在 CKD 条件下鸢尾素、细胞焦亡和 VC 之间的潜在联系。在β-甘油磷酸（β-GP）诱导的小鼠血管平滑肌细胞（VSMC）钙化过程中，细胞焦亡水平增加，这表现在细胞焦亡相关蛋白（裂解 CASP1、GSDMD-N 和 IL1B）和焦亡性细胞死亡（PI 阳性细胞数量增加和 LDH 释放增加）的表达上调。用 CASP1 抑制剂降低细胞焦亡水平可显著减少 β-GP 处理的 VSMC 中的钙沉积。进一步的实验表明，在钙化的 VSMC 中，过量的活性氧（ROS）产生和随后的 NOD、LRR 和富含亮氨酸重复序列家族蛋白 3（NLRP3）炎性小体激活激活了细胞焦亡途径。重要的是，鸢尾素在体外和小鼠主动脉环中有效抑制了β-GP 诱导的 VSMC 钙化。Nlrp3 的过表达减弱了鸢尾素对 VSMC 钙化的抑制作用。此外，鸢尾素可诱导自噬并恢复钙化的 VSMC 中的自噬流。添加自噬抑制剂 3-甲基腺嘌呤或氯喹减弱了鸢尾素对β-GP 诱导的 ROS 产生、NLRP3 炎性小体激活、细胞焦亡和 VSMC 钙化的抑制作用。最后，我们的体内研究表明，鸢尾素治疗可促进自噬，降低 ROS 水平，从而抑制 CKD 诱导的腺嘌呤小鼠主动脉组织中的细胞焦亡和中膜钙化。总之，我们的研究结果首次表明，鸢尾素通过诱导自噬和抑制 CKD 中 VSMC 细胞焦亡来保护 VC，并且鸢尾素可能成为治疗 CKD 相关 VC 的有效治疗剂。
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