CROCIN ALLEVIATES MYOCARDIAL ISCHEMIA/ REPERFUSION-INDUCED ENDOPLASMIC RETICULUM STRESS VIA REGULATION OF MIR-34A/SIRT1/NRF2 PATHWAY
CROCIN ALLEVIATES MYOCARDIAL ISCHEMIA/ REPERFUSION-INDUCED ENDOPLASMIC RETICULUM STRESS VIA REGULATION OF MIR-34A/SIRT1/NRF2 PATHWAY
复制标题
藏红花素通过调节 MIR-34A/SIRT1/NRF2 通路缓解心肌缺血/再灌注引起的内质网应激
DOI：
10.1097/shk.0000000000001116
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发表时间：
2019
期刊：
影响因子：
3.1
通讯作者：
Gong Gu
中科院分区：
文献类型：
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作者：
Wang Xiaowu;Yuan Binbin;Cheng Biao;Liu Ying;Zhang Ben;Wang Xianyue;Lin Xi;Yang Bo;Gong Gu
内质网应激与缺血再灌注(I/R)诱导的心肌细胞凋亡有关。西红花苷可保护心肌细胞免受I/R损伤，抑制内质网应激。本研究旨在探讨西红花苷在心肌I/R损伤中参与内质网应激的分子机制。我们发现西红花苷可减轻I/R诱导的原代心肌细胞和小鼠模型心肌细胞的凋亡。西红花苷可降低I/R损伤诱导的Bax、活性caspase 3、78 kDa葡萄糖调节蛋白(GRP78)和C/EBP同源蛋白(CHOP)的表达，而上调Bc l-2的表达，这种作用可被内质网应激激活剂thapsigargin阻断。在I/R诱导的心肌细胞中，西红花酸降低miR-34a的表达，而增加Sirt1、Nrf2和HO-1的水平。MiR-34a过表达降低了Sirt1、Nrf2和HO-1的表达；相反，miR-34a的抑制上调了它们的表达。SIRT1阻断剂烟酰胺和Nrf2 siRNA可抑制GRP78、CHOP、Bax和活性caspase3的表达。在I/R诱导的小鼠模型中，凋亡和内质网应激相关蛋白的水平以及miR-34a、Sirt1、Nrf2和HO-1的表达与体外模型一致。此外，西红花苷可减轻I/R所致的小鼠左心功能不全和心肌梗死。结论：西红花苷通过抑制受miR-34a/Sirt1/Nrf2途径调控的内质网应激来减轻I/R诱导的心肌细胞凋亡。
Endoplasmic reticulum (ER) stress is associated with ischemia/reperfusion (I/R)-induced cardiomyocyte apoptosis. Crocin could protect myocardial cells against I/R injury and suppress ER stress. This study aimed to explore the molecular mechanism of crocin related to ER stress in myocardial I/R injury. We found crocin alleviated I/R-induced cardiomyocyte apoptosis both in I/R-induced primary cardiomyocytes and in mouse models. The expression of Bax, active caspase 3, glucose-regulated protein of 78 kDa (GRP78), and C/EBP homologous protein (CHOP) induced by I/R injury was reduced, whereas Bcl-2 expression was enhanced by crocin, the effect of which was abrogated by ER stress activator thapsigargin treatment. Crocin decreased miR-34a expression, whereas it increased Sirt1, Nrf2, and HO-1 levels, in I/R-induced cardiomyocytes. miR-34a overexpression reduced the expression of Sirt1, Nrf2, and HO-1; in contrast, the suppression of miR-34a upregulated their expression. Sirt1 blocker nicotinamide and Nrf2 siRNA restrained the levels of GRP78, CHOP, Bax, and active caspase 3. The levels of apoptosis-and ER stress-related proteins, and the expression of miR-34a, Sirt1, Nrf2, and HO-1 in I/R-induced mouse models were consistent with those in vitro. In addition, I/R-induced left ventricular dysfunction and infarct were attenuated by crocin in mice. In conclusion, crocin attenuates I/R-induced cardiomyocyte apoptosis via suppressing ER stress, which is regulated by the miR-34a/Sirt1/Nrf2 pathway.