Up-regulation of heme oxygenase-1 by celastrol alleviates oxidative stress and vascular calcification in chronic kidney disease
Up-regulation of heme oxygenase-1 by celastrol alleviates oxidative stress and vascular calcification in chronic kidney disease
复制标题
雷公藤红醇上调血红素加氧酶-1 可减轻慢性肾脏病中的氧化应激和血管钙化。
DOI：
10.1016/j.freeradbiomed.2021.06.020
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发表时间：
2021-07-08
影响因子：
7.4
通讯作者：
Yan, Jianyun
中科院分区：
文献类型：
--
作者：
Yang, Xiulin;Chen, An;Yan, Jianyun
血管钙化在慢性肾脏病(CKD)患者中非常常见，但目前还没有有效的治疗方法。氧化应激在血管钙化过程中起着关键作用。雷公藤红素(CEL)是一种从中草药中提取的天然成分，具有抗氧化应激活性。在这里，我们利用血管平滑肌细胞(VSMCs)、动脉环和CKD大鼠研究了雷公藤红素对血管钙化的影响。茜素红染色和基因表达分析表明，CEL呈剂量依赖性抑制大鼠VSMC钙化和成骨分化。同样，体外研究表明，CEL抑制了大鼠和人动脉环的钙化。此外，计算机断层扫描、茜素红染色和钙含量分析证实，CEL可抑制CKD大鼠的主动脉钙化。有趣的是，CEL处理提高了VSMCs中HMOX-1的mRNA和蛋白水平，降低了VSMC中的ROS水平。此外，对HMOX-1的药理抑制和siRNA对HMOX-1的抑制都独立地抵消了CEL对血管钙化的抑制作用。此外，HMOX-1的敲除阻止了CEL治疗介导的ROS水平的降低。最后，CEL治疗减少了维生素D3诱导的小鼠主动脉钙化，这一作用可被HMOX-1抑制剂ZnPP9阻断。综上所述，我们的结果表明，HMOX-1的上调是CEL抑制血管钙化所必需的。HMOX-1的调控可能为慢性肾脏病血管钙化的治疗提供新的策略。
Vascular calcification is very commonly observed in patients with chronic kidney disease (CKD), but there is no efficient therapy available. Oxidative stress plays critical roles in the progression of vascular calcification. Celastrol (Cel), a natural constituent derived from Chinese herbals, exhibits anti-oxidative stress activity. Here, we investigated the effect of celastrol on vascular calcification using vascular smooth muscle cells (VSMCs), arterial rings and CKD rats. Alizarin red staining and gene expression analysis showed that Cel dose-dependently inhibited rat VSMC calcification and osteogenic differentiation. Similarly, ex vivo study revealed that Cel inhibited calcification of rat and human arterial rings. In addition, micro-computed tomography, alizarin red staining and calcium content analysis confirmed that Cel inhibited aortic calcification in CKD rats. Interestingly, Cel treatment increased the mRNA and protein levels of heme oxygenase-1 (HMOX-1), and reduced the levels of reactive oxygen species (ROS) in VSMCs. Furthermore, both pharmacological inhibition of HMOX-1 and knockdown of HMOX-1 by siRNA independently counteracted the inhibitory effect of Cel on vascular calcification. Moreover, knockdown of HMOX-1 prevented Cel treatment-mediated reduction in ROS levels. Finally, Cel treatment reduced Vitamin D3-induced aortic calcification in mice and this effect was blocked by HMOX-1 inhibitor ZnPP9. Collectively, our results suggest that up-regulation of HMOX-1 is required for the inhibitory effect of Cel on vascular calcification. Modulation of HMOX-1 may provide a novel strategy for the treatment of vascular calcification in CKD.