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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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Abstract

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-1α (IRE1α) in H9c2 cells. Finally, we found that ATF6 siRNA, PERK siRNA or IRE1α 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, IRE1α and PERK signaling activation.

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Acknowledgments

The present study was supported by the National Natural Science Foundation of China (No. 81470500 and 81600240), the Distinguished Young Scholar Cultivation Project of Xijing Hospital (XJZT14J03), and National Natural Science Foundation of China (No.81600295).

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    Authors and Affiliations

    1. Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 169 W Changle West Road, Xi’an, 710032, Shanxi, People’s Republic of China

      Jia-You Tang, Ping Jin, Qing He, Lin-He Lu, Ji-Peng Ma & Jian Yang

    2. Department of Cardiovascular Surgery, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, People’s Republic of China

      Wei-Lun Gao

    3. Department of Thoracic and Cardiovascular Surgery, The Second Hospital of Yulin, Yulin, 719000, Shanxi, People’s Republic of China

      He-Ping Bai

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    Jia-you Tang and Ping Jin have contributed equally to this work.

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    Tang, JY., Jin, P., He, Q. et al. Naringenin ameliorates hypoxia/reoxygenation-induced endoplasmic reticulum stress-mediated apoptosis in H9c2 myocardial cells: involvement in ATF6, IRE1α and PERK signaling activation. Mol Cell Biochem 424, 111–122 (2017). https://doi.org/10.1007/s11010-016-2848-1

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