Naringenin ameliorates hypoxia/reoxygenation-induced endoplasmic reticulum stress-mediated apoptosis in H9c2 myocardial cells: involvement in ATF6, IRE1α and PERK signaling activation

Tang, Jiayou; Park, Jin; He, Qing; Lu, Linhe; Ma, Jie; Gao, Wei-Lun; Bai, He-Ping; Yang, Jian

doi:10.1007/s11010-016-2848-1

Cited by 40 publications

(22 citation statements)

References 53 publications

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“…Naringenin treatment restored cell viability, cell morphology, normalized BCL-2, BAX and caspase 3 in I/R-treated H9c2 cells. Likewise, the protective effect of naringenin against I/R injury is due to inhibition of ER stress-mediated apoptosis, which potentially involves activation of transcription factor 6 (ATF6), inositol-requiring enzyme-1α (IRE1α) and phosphoextracellular regulated protein kinases (PERK) [85]. Thus, pretreatment of H9c2 cells with naringenin promoted the reduction of ER-mediated apoptotic cell death and lipid peroxidation, and showed increased level of reduced glutathione when these cells were submitted to an oxidative insult such as H2O2.…”

Section: Flavanonesmentioning

confidence: 99%

Pure Polyphenols Applications for Cardiac Health and Disease

Santos

Gomes

Oudot

et al. 2018

CPD

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Polyphenols are natural compounds present in fruits and vegetables that can exert beneficial effects on human health and notably, on the cardiovascular system. Some of these compounds showed significant protective activities toward atherosclerosis, hypertension, myocardial infarction, anthracyclin-induced cardiomyopathy, angiogenesis as well as heart failure. Polyphenols can act through systemic effects as well as through modulation of signaling pathways such as redox signaling, inflammation, autophagy and cell death in the heart and vessels. These effects can be mediated by changes in expression level and by post-translational modifications of proteins (e.g. Stat1, CaMKII, Sirtuins, BCL-2 family members, PDEs, TRF2, eNOS and SOD). This non-comprehensive short review aims to summarize recent knowledge on the main pharmacological effects and mechanisms of cardioprotection of pure polyphenols, using different approaches such as cell culture, animal models and human studies.

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Section: Flavanonesmentioning

confidence: 99%

Pure Polyphenols Applications for Cardiac Health and Disease

Santos

Gomes

Oudot

et al. 2018

CPD

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“…Hibernators survive repeated cycles of IR (6,7), while IR injury contributes to the pathogenesis of a number of human diseases (1-3), AKI included (4,5). IR induces ER stress, which may cause cell death in various cell types, including RPTECs (18)(19)(20)(21)(22). This study aimed to elucidate the mechanisms through which RPTECs derived from the native hibernator Syrian hamster cope with ER stress.…”

Section: Discussionmentioning

confidence: 99%

“…Since IR triggers ER stress-induced cell death in myocardial (18,19), neural (20), and interestingly, in renal tubular epithelial cells (21,22), this study aimed to evaluate the unique characteristics of IR-induced ER stress, and specifically of ER-associated protein degradation, in renal proximal tubular epithelial cells (RPTECs) of the native hibernator Syrian hamster compared to human-derived RPTECs. Mouse-derived RPTECs were also evaluated as a phylogenetic control for hamster-derived RPTECs.…”

Section: Introductionmentioning

confidence: 99%

Renal tubular epithelial cells of the native hibernator Syrian hamster recover more rapidly from endoplasmic reticulum stress compared to those of human or mouse following warm anoxia-reoxygenation, possibly due to increased proteasomal function

Eleftheriadis

Pissas

Antoniadi

et al. 2018

wasj

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Comparative biology may reveal novel therapeutic strategies against human diseases. Ischemia‑reperfusion (IR) injury induces a number of diseases. It is known that hibernating mammals survive IR since during hibernation, prolonged periods of torpor with a marked decrease in blood flow and breathing rate are interrupted by short periods of arousal. In the present study, the differences in the characteristics of endoplasmic reticulum (ER) stress and the subsequent unfolded protein response, which are induced by IR and may cause cell death among humans, mice or the native hibernator Syrian hamster were examined in vitro using renal proximal tubular epithelial cells (RPTECs) derived from these three sources. RPTECs were subjected to anoxia or reoxygenation, both at 37˚C. Cell death was measured by LDH release assay. ER stress was assessed by determining the levels of phosphorylated protein kinase RNA‑like ER kinase, ubiquitinated proteins and Bcl‑2‑associated X protein (Bax) by western blot analysis. For proteasomal activity, a specific assay was used. The results revealed that anoxia induced ER stress in all the evaluated RPTECs, from which only the hamster‑derived RPTECs recovered during reoxygenation. Anoxia and reoxygenation increased protein ubiquitination in the human‑ and mouse‑derived RPTECs, whereas this was decreased in the hamster‑derived RPTECs. Anoxia enhanced proteasomal activity in all the evaluated RPTECs. In the human‑ and mouse‑derived RPTECs, reoxygenation reduced proteasomal activity, which remained high in the hamster‑derived RPTECs. Anoxia and reoxygenation increased Bax expression and induced cell death in the human‑ and mouse‑derived RPTECs, while neither Bax overexpression nor cell death occurred in the hamster‑derived RPTECs. Thus, on the whole, the findings of this study demonstrate that compared to human‑ or mouse‑derived RPTECs, those derived from the hamster recover more rapidly from ER stress following warm anoxia‑reoxygenation, possibly due to increased proteasomal function.

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“…For example, one study by Meng et al demonstrated that naringenin protected against MI/R injury through activating ATP-sensitive potassium channels and enhancing myocardial antioxidant capacity [18]. Intriguingly, in cultured H9c2 cells, Tang and coworkers found that naringenin regulated cellular ER stress level and attenuated hypoxia/reoxygenation-induced cytotoxicity [19]. However, the detailed mechanisms of naringenin's inhibitory effects against oxidative stress injury under MI/R conditions remain uncovered.…”

Section: Introductionmentioning

confidence: 99%

Naringenin Attenuates Myocardial Ischemia-Reperfusion Injury via cGMP-PKGIα Signaling and In Vivo and In Vitro Studies

Dong

Zhang

et al. 2019

Oxidative Medicine and Cellular Longevity

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Endoplasmic reticulum (ER) stress and oxidative stress contribute greatly to myocardial ischemia-reperfusion (MI/R) injury. Naringenin, a flavonoid derived from the citrus genus, exerts cardioprotective effects. However, the effects of naringenin on ER stress as well as oxidative stress under MI/R condition and the detailed mechanisms remain poorly defined. This study investigated the protective effect of naringenin on MI/R-injured heart with a focus on cyclic guanosine monophosphate- (cGMP-) dependent protein kinase (PKG) signaling. Sprague-Dawley rats were treated with naringenin (50 mg/kg/d) and subjected to MI/R surgery with or without KT5823 (2 mg/kg, a selective inhibitor of PKG) cotreatment. Cellular experiment was conducted on H9c2 cardiomyoblasts subjected to simulated ischemia-reperfusion treatment. Before the treatment, the cells were incubated with naringenin (80 μmol/L). PKGIα siRNA was employed to inhibit PKG signaling. Our in vivo and in vitro data showed that naringenin effectively improved heart function while it attenuated myocardial apoptosis and infarction. Furthermore, pretreatment with naringenin suppressed MI/R-induced oxidative stress as well as ER stress as evidenced by decreased superoxide generation, myocardial MDA level, gp91phox expression, and phosphorylation of PERK, IRE1α, and EIF2α as well as reduced ATF6 and CHOP. Importantly, naringenin significantly activated myocardial cGMP-PKGIα signaling while inhibition of PKG signaling with KT5823 (in vivo) or siRNA (in vitro) not only abolished these actions but also blunted naringenin's inhibitory effects against oxidative stress and ER stress. In summary, our study demonstrates that naringenin treatment protects against MI/R injury by reducing oxidative stress and ER stress via cGMP-PKGIα signaling. Its cardioprotective effect deserves further clinical study.

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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

Cited by 40 publications

References 53 publications

Pure Polyphenols Applications for Cardiac Health and Disease

Pure Polyphenols Applications for Cardiac Health and Disease

Renal tubular epithelial cells of the native hibernator Syrian hamster recover more rapidly from endoplasmic reticulum stress compared to those of human or mouse following warm anoxia-reoxygenation, possibly due to increased proteasomal function

Naringenin Attenuates Myocardial Ischemia-Reperfusion Injury via cGMP-PKGIα Signaling and In Vivo and In Vitro Studies

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