Spermidine inhibits vascular calcification in chronic kidney disease through modulation of SIRT1 signaling pathway.
Spermidine inhibits vascular calcification in chronic kidney disease through modulation of SIRT1 signaling pathway.
复制标题
亚精胺通过调节 SIRT1 信号通路抑制慢性肾脏疾病中的血管钙化。
作者：
Liu X;Chen A;Liang Q;Yang X;Dong Q;Fu M;Wang S;Li Y;Ye Y;Lan Z;Chen Y;Ou JS;Yang P;Lu L;Yan J
血管钙化是慢性肾病（CKD）患者和老年人常见的病理状态。已经确定血管钙化是一种基因调控的生物学过程，类似于涉及成骨分化的骨生成。然而，迄今为止，对于血管钙化没有有效的治疗方法。天然多胺亚精胺已被证明可以延长寿命和预防心血管疾病。目前尚不清楚亚精胺补充剂是否能抑制CKD患者的血管钙化。茜素红染色和定量钙含量表明，亚精胺治疗显着减少矿物质沉积在大鼠和人血管平滑肌细胞（VSMCs）成骨条件下。此外，蛋白质印迹分析显示亚精胺处理抑制大鼠和人VSMCs的成骨分化。此外，亚精胺治疗显着衰减钙化大鼠和人类动脉环离体和主动脉钙化大鼠CKD。此外，亚精胺处理诱导VSMCs中Sirtuin 1（SIRT 1）的上调，并导致内质网（ER）应激信号传导组分的下调，如激活转录因子4（ATF 4）和CCAAT/增强子结合蛋白同源蛋白（CHOP）。SIRT 1抑制剂EX 527对SIRT 1的药理学抑制和siRNA对SIRT 1的敲低均显著阻断亚精胺对VSMC钙化的抑制作用。因此，EX 527消除了亚精胺对CKD大鼠主动脉钙化的抑制作用。我们首次证明亚精胺通过上调SIRT 1和抑制ER应激来减轻CKD中的血管钙化，这可能会开发出一种有前途的治疗方法来改善CKD中的血管钙化。本文报道亚精胺（Spd）对慢性肾病（CKD）大鼠血管平滑肌细胞、动脉环和动脉粥样硬化的抑制作用。此外，SIRT 1信号对于Spd在血管钙化中的抑制作用至关重要。总之，这些发现提供了第一个证据表明，Spd通过调节SIRT 1和ER应激信号抑制动脉钙化，表明Spd可能作为一种新的SIRT 1调节剂来治疗动脉钙化。
Vascular calcification is a common pathologic condition in patients with chronic kidney disease (CKD) and aging individuals. It has been established that vascular calcification is a gene‐regulated biological process resembling osteogenesis involving osteogenic differentiation. However, there is no efficient treatment available for vascular calcification so far. The natural polyamine spermidine has been demonstrated to increase life span and protect against cardiovascular disease. It is unclear whether spermidine supplementation inhibits vascular calcification in CKD. Alizarin red staining and quantification of calcium content showed that spermidine treatment markedly reduced mineral deposition in both rat and human vascular smooth muscle cells (VSMCs) under osteogenic conditions. Additionally, western blot analysis revealed that spermidine treatment inhibited osteogenic differentiation of rat and human VSMCs. Moreover, spermidine treatment remarkably attenuated calcification of rat and human arterial rings ex vivo and aortic calcification in rats with CKD. Furthermore, treatment with spermidine induced the upregulation of Sirtuin 1 (SIRT1) in VSMCs and resulted in the downregulation of endoplasmic reticulum (ER) stress signaling components, such as activating transcription factor 4 (ATF4) and CCAAT/enhancer‐binding protein homologous protein (CHOP). Both pharmacological inhibition of SIRT1 by SIRT1 inhibitor EX527 and knockdown of SIRT1 by siRNA markedly blocked the inhibitory effect of spermidine on VSMC calcification. Consistently, EX527 abrogated the inhibitory effect of spermidine on aortic calcification in CKD rats. We for the first time demonstrate that spermidine alleviates vascular calcification in CKD by upregulating SIRT1 and inhibiting ER stress, and this may develop a promising therapeutic treatment to ameliorate vascular calcification in CKD. We reported that spermidine (Spd) inhibits calcification of vascular smooth muscle cells, arterial rings and aortas in rats with chronic kidney disease (CKD). Furthermore, SIRT1 signal is critical for the inhibitory role of Spd in vascular calcification. Taken together, these findings provide the first evidence that Spd inhibits arterial calcification through modulation of SIRT1 and ER stress signals, suggesting that Spd may act as a novel SIRT1 modulator to treat arterial calcification.
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影响因子：
10.8
作者：
Durham AL;Speer MY;Scatena M;Giachelli CM;Shanahan CM
通讯作者：
Shanahan CM
DOI：
10.1161/atvbaha.118.311874
发表时间：
2019-03-01
影响因子：
8.7
作者：
Lee, Guan-Lin;Yeh, Chang-Ching;Kuo, Cheng-Chin
通讯作者：
Kuo, Cheng-Chin
影响因子：
3.5
作者：
Hsu, Yu-Juei;Hsu, Shih-Che;Lin, Chih-Yuan
通讯作者：
Lin, Chih-Yuan
影响因子：
3.2
作者：
Eid, Refaat A.;Alharbi, Samah A.;Al-Shudiefat, Abd Al-Rahman Salem
通讯作者：
Al-Shudiefat, Abd Al-Rahman Salem
影响因子：
1.9
作者：
Shanahan CM;Furmanik M
通讯作者：
Furmanik M