Irisin protects against vascular calcification by activating autophagy and inhibiting NLRP3-mediated vascular smooth muscle cell pyroptosis in chronic kidney disease.
Irisin protects against vascular calcification by activating autophagy and inhibiting NLRP3-mediated vascular smooth muscle cell pyroptosis in chronic kidney disease.
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鸢尾素通过激活自噬并抑制慢性肾脏病中 NLRP3 介导的血管平滑肌细胞焦亡来防止血管钙化
DOI：
10.1038/s41419-022-04735-7
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发表时间：
2022-03-30
影响因子：
9
通讯作者：
Zhang A
中科院分区：
文献类型：
--
作者：
Pang Q;Wang P;Pan Y;Dong X;Zhou T;Song X;Zhang A
Irisin保护心血管系统免受血管疾病。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仍不清楚。在本研究中，我们调查了CKD条件下Irisin、焦亡和VC之间的潜在联系。在β-甘油磷酸盐（β-GP）诱导的小鼠血管平滑肌细胞（VSMC）钙化过程中，细胞凋亡水平增加，表现为细胞凋亡相关蛋白（CASP 1、GSDMD-N和IL 1B）表达上调和细胞凋亡（PI阳性细胞和LDH释放增加）。通过CASP 1抑制剂降低细胞凋亡水平可显著降低β-GP处理的VSMCs中的钙沉积。进一步的实验表明，在钙化的VSMC中，过度的活性氧（ROS）产生和随后的NLR家族pyrin结构域3（NLRP 3）炎性小体激活了焦亡途径。重要的是，Irisin在体外有效抑制β-GP诱导的VSMCs和离体小鼠主动脉环中的钙沉积。Nlrp 3过表达可减弱Irisin对VSMC钙化的抑制作用。此外，Irisin可诱导钙化的VSMCs自噬并恢复自噬流量。加入自噬抑制剂3-甲基腺嘌呤或氯喹减弱了Irisin对β-GP诱导的VSMCs ROS产生、NLRP 3炎性小体激活、焦亡和钙化的抑制作用。最后，我们的体内研究表明，鸢尾素治疗促进自噬，下调ROS水平，从而抑制腺嘌呤诱导的CKD小鼠主动脉组织中的焦亡和中膜钙化。总之，我们的研究结果首次表明，Irisin通过诱导自噬和抑制CKD中VSMC的焦亡来保护VC，并且Irisin可能作为CKD相关VC的有效治疗剂。
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 ofNlrp3attenuated 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.
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影响因子：
5.6
作者：
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通讯作者：
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影响因子：
4.5
作者：
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