Naringenin ameliorates hypoxia/reoxygenation-induced endoplasmic reticulum stress-mediated apoptosis in H9c2 myocardial cells: involvement in ATF6, IRE1α and PERK signaling activation
Naringenin ameliorates hypoxia/reoxygenation-induced endoplasmic reticulum stress-mediated apoptosis in H9c2 myocardial cells: involvement in ATF6, IRE1α and PERK signaling activation
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柚皮素改善 H9c2 心肌细胞缺氧/复氧诱导的内质网应激介导的细胞凋亡：参与 ATF6、IRE1α 和 PERK 信号激活
DOI：
10.1007/s11010-016-2848-1
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发表时间：
2017-01-01
影响因子：
4.3
通讯作者：
Yang, Jian
中科院分区：
文献类型：
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作者：
Tang, Jia-You;Jin, Ping;Yang, Jian
柚皮素是一种主要从葡萄和柑橘类水果中提取的黄酮，据报道具有保护心脏的作用。越来越多的证据证实内质网应激介导的凋亡参与心肌缺血/再灌注损伤过程，抑制内质网应激是预防心血管疾病的潜在治疗靶点/策略。本研究旨在探讨柚皮素是否通过减轻内质网应激或内质网应激介导的凋亡来保护H9c2心肌细胞免受缺氧/再氧化（H/R）损伤。结果表明，柚皮素可显著提高H9c2细胞活力和抗凋亡蛋白Bcl-2的表达，降低H/ r处理的H9c2细胞凋亡形态学变化、caspase-3活性和促凋亡蛋白Bax的表达，提示柚皮素对H/ r诱导的损伤具有保护作用。此外，柚皮素还通过上调葡萄糖调节蛋白78、C/EBP同源蛋白和Cleaved caspase-12蛋白，显著逆转H/ r诱导的内质网应激。同时，柚皮素显著逆转H/ r诱导的H9c2细胞中劈裂激活转录因子6 （ATF6）表达升高、磷酸化细胞外调节蛋白激酶（PERK）和肌醇需要酶-1 α (IRE1 α)磷酸化水平升高。最后，我们发现ATF6 siRNA、PERK siRNA或IRE1 α siRNA可消除H/ r诱导的H9c2细胞毒性和凋亡。综上所述，这些结果证实了内质网应激介导的凋亡参与了柚皮素对H/R损伤的保护作用，其可能参与了ATF6、IRE1 α和PERK信号的激活。
Naringenin, a flavanone mainly derived from grapes and citrus fruits, has been reported to exhibit cardioprotective effects. Accumulating evidence has confirmed that endoplasmic reticulum (ER) stress-mediated apoptosis participates in the process of myocardial ischemia/reperfusion injury and inhibiting ER stress is a potential therapeutic target/strategy in preventing cardiovascular diseases. Herein, the current study was designed to investigate whether naringenin protects H9c2 myocardial cells against hypoxia/reoxygenation (H/R) injury via attenuating ER stress or ER stress-mediated apoptosis. Our results showed that naringenin treatment resulted in obvious increases in the viability of H9c2 cells and the expression of Bcl-2 (anti-apoptotic protein), and decreases in the morphological changes of apoptotic cells, the activity of caspase-3 and the expression of Bax (pro-apoptotic protein) in H/R-treated H9c2 cells, implying the protective effects of naringenin against H/R-induced injury. In addition, naringenin also significantly reversed H/R-induced ER stress as evidenced by the up-regulation of Glucose-regulated protein 78, C/EBP homologous protein and Cleaved caspase-12 proteins. Meanwhile, naringenin remarkably reversed H/R-induced the increases in the expression of cleaved activating transcription factor 6 (ATF6) and phosphorylation levels of phospho-extracellular regulated protein kinases (PERK) and inositol-requiring enzyme-1 alpha (IRE1 alpha) in H9c2 cells. Finally, we found that ATF6 siRNA, PERK siRNA or IRE1 alpha siRNA abolished H/R-induced cytotoxicity and apoptosis in H9c2 cells. In conclusion, these results confirmed that ER stress-mediated apoptosis contributes to the protection effects of naringenin against H/R injury, which is potentially involved in ATF6, IRE1 alpha and PERK signaling activation.