title: Naringenin ameliorates hypoxia/reoxygenation-induced endoplasmic reticulum stress-mediated apoptosis in H9c2 myocardial cells: involvement in ATF6, IRE1α and PERK signaling activation.
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.
authors: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 169 W Changle West Road, Xi'an, 710032, Shanxi, People's Republic of China.
authors: Jia-You
authors: JY
authors: Tang
authors: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 169 W Changle West Road, Xi'an, 710032, Shanxi, People's Republic of China.
authors: Ping
authors: P
authors: Jin
authors: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 169 W Changle West Road, Xi'an, 710032, Shanxi, People's Republic of China.
authors: Qing
authors: Q
authors: He
authors: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 169 W Changle West Road, Xi'an, 710032, Shanxi, People's Republic of China.
authors: Lin-He
authors: LH
authors: Lu
authors: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 169 W Changle West Road, Xi'an, 710032, Shanxi, People's Republic of China.
authors: Ji-Peng
authors: JP
authors: Ma
authors: Department of Cardiovascular Surgery, General Hospital of Ningxia Medical University, Yinchuan, 750004, Ningxia, People's Republic of China.
authors: Wei-Lun
authors: WL
authors: Gao
authors: Department of Thoracic and Cardiovascular Surgery, The Second Hospital of Yulin, Yulin, 719000, Shanxi, People's Republic of China.
authors: He-Ping
authors: HP
authors: Bai
authors: Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, 169 W Changle West Road, Xi'an, 710032, Shanxi, People's Republic of China. yangjian0169@qq.com.
authors: Jian
authors: J
authors: Yang
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004722:Endoribonucleases / Q000378:metabolism*; D044950:Flavanones / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000378:metabolism*; D032383:Myocytes, Cardiac; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D051702:Activating Transcription Factor 6; D004722:Endoribonucleases; D044950:Flavanones; D009097:Multienzyme Complexes; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C497113:Atf6 protein, rat; C575026:Ern1 protein, rat; C005273:naringenin
keywords: Apoptosis; Cardioprotection; Endoplasmic reticulum stress; Hypoxia/reoxygenation injury; Naringenin