scholarly journals FGF-2 Transcriptionally Down-Regulates the Expression of BNIP3L via PI3K/Akt/FoxO3a Signaling and Inhibits Necrosis and Mitochondrial Dysfunction Induced by High Concentrations of Hydrogen Peroxide in H9c2 Cells

2016 ◽  
Vol 40 (6) ◽  
pp. 1678-1691 ◽  
Author(s):  
Qian Chen ◽  
Xiaosong Chen ◽  
Conghui Han ◽  
Ying Wang ◽  
Tao Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Disease ◽  
Mitochondrial Dysfunction ◽  
Gene Promoter ◽  
Luciferase Assay ◽  
Protective Effects ◽  
H9c2 Cells ◽  
Akt Inhibitor ◽  
H9c2 Cardiomyocytes ◽  
H9c2 Cardiomyoblast Cells

Background/Aims: Cardiovascular disease is a growing major global public health problem. Necrosis is one of the main forms of cardiomyocyte death in heart disease. Oxidative stress is regarded as one of the key regulators of cardiac necrosis, which eventually leads to cardiovascular disease. Many pharmacological and in vitro studies have suggested that FGF-2 can act directly on cardiomyocytes to maintain the integrity and function of the myocardium and prevent damage during oxidative stress. However, the mechanisms by which FGF-2 rescues the myocardium from oxidative stress damage in cardiovascular disease remain unclear. The present study explored the protective effects of FGF-2 in the H2O2-induced necrosis of H9C2 cardiomyocytes as well as the possible signaling pathways involved. Methods: Necrosis of H9c2 cardiomyocytes was induced by H2O2 and assessed using a Cell Counting Kit-8 (CCK8) assay and flow cytometry analysis. The cells were pretreated with the PI3K/Akt inhibitor Wortmannin to investigate the possible involvement of the PI3K/Akt pathway in the protection by FGF-2. The levels of Akt, p-Akt, FoxO3a, p-FoxO3a, and BNIP3L were detected by Western blot. Chromatin immuno-precipitation (ChIP) analysis was used to test whether FoxO3a binds directly to the BNIP3L promoter region. A luciferase assay was used to study the effects of FoxO3a on BNIP3L gene promoter activity. Mitochondrial ΔΨM was quantified using tetramethylrhodamine methyl ester perchlorate (TMRM). The mitochondrial oxygen consumption rate (OCR) was assessed with a Seahorse XF24 Analyzer. Results: Treatment with H2O2 decreased the phosphorylation of Akt and FoxO3a, and it induced the nuclear localization of FoxO3a and the necrosis of H9c2 cells. These effects of H2O2 were abrogated by pretreatment with FGF-2. Furthermore, the protective effects of FGF-2 were abolished by the PI3K/Akt inhibitor Wortmannin. ChIP analyses indicated that FoxO3a binds directly to the BNIP3L promoter region. Using a luciferase assay, we further observed that FoxO3a increased BNIP3L gene promoter activity. As expected, overexpression of BNIP3L in H9C2 cardiomyoblast cells reduced the cardioprotection of FGF-2 in H2O2-induced necrosis and mitochondrial dysfunction. Conclusions: The present data suggest that FGF-2 protects against H2O2-induced necrosis of H9C2 cardiomyocytes via the activation of the PI3K/Akt/FoxO3a pathway. Moreover, the present results demonstrate that FoxO3a is an important transcription factor that acts by binding to the promoter and promoting the transcription of BNIP3L, and it contributes to the necrosis and mitochondrial dysfunction induced by H2O2 in H9c2 cardiomyoblast cells.

scholarly journals L-Carnitine: An Antioxidant Remedy for the Survival of Cardiomyocytes under Hyperglycemic Condition

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Fernanda Vacante ◽  
Pamela Senesi ◽  
Anna Montesano ◽  
Alice Frigerio ◽  
Livio Luzi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Signaling Pathways ◽  
Stress Condition ◽  
Cardiac Cells ◽  
Ros Production ◽  
Protective Effects ◽  
H9c2 Cells ◽  
Rat Cardiomyocytes ◽  
Oxidative Stress Condition

Background. Metabolic alterations as hyperglycemia and inflammation induce myocardial molecular events enhancing oxidative stress and mitochondrial dysfunction. Those alterations are responsible for a progressive loss of cardiomyocytes, cardiac stem cells, and consequent cardiovascular complications. Currently, there are no effective pharmacological measures to protect the heart from these metabolic modifications, and the development of new therapeutic approaches, focused on improvement of the oxidative stress condition, is pivotal. The protective effects of levocarnitine (LC) in patients with ischemic heart disease are related to the attenuation of oxidative stress, but LC mechanisms have yet to be fully understood. Objective. The aim of this work was to investigate LC’s role in oxidative stress condition, on ROS production and mitochondrial detoxifying function in H9c2 rat cardiomyocytes during hyperglycemia. Methods. H9c2 cells in the hyperglycemic state (25 mmol/L glucose) were exposed to 0.5 or 5 mM LC for 48 and 72 h: LC effects on signaling pathways involved in oxidative stress condition were studied by Western blot and immunofluorescence analysis. To evaluate ROS production, H9c2 cells were exposed to H2O2 after LC pretreatment. Results. Our in vitro study indicates how LC supplementation might protect cardiomyocytes from oxidative stress-related damage, preventing ROS formation and activating antioxidant signaling pathways in hyperglycemic conditions. In particular, LC promotes STAT3 activation and significantly increases the expression of antioxidant protein SOD2. Hyperglycemic cardiac cells are characterized by impairment in mitochondrial dysfunction and the CaMKII signal: LC promotes CaMKII expression and activation and enhancement of AMPK protein synthesis. Our results suggest that LC might ameliorate metabolic aspects of hyperglycemic cardiac cells. Finally, LC doses herein used did not modify H9c2 growth rate and viability. Conclusions. Our novel study demonstrates that LC improves the microenvironment damaged by oxidative stress (induced by hyperglycemia), thus proposing this nutraceutical compound as an adjuvant in diabetic cardiac regenerative medicine.

scholarly journals microRNA-223-3p attenuates angiotensin II-dependent ROS effect on cell viability by targeting NLRP3 in H9c2 cells

2021 ◽  
Author(s):  
Weiran Dai ◽  
Shuang Zhou ◽  
Guoqiang Zhong ◽  
Zhiyuan Jiang
Keyword(s):  
Oxidative Stress ◽  
Cell Viability ◽  
Nlrp3 Inflammasome ◽  
Right Atrial ◽  
Luciferase Assay ◽  
Ros Generation ◽  
H9c2 Cell ◽  
Protective Effects ◽  
Ang Ii ◽  
H9c2 Cells

IntroductionRecently, enhanced activation of NLRP3 has been reported to be involved in atrial fibrillation (AF). This study aimed to detect the correlation between oxidative stress and NLRP3 and explore the role of miR-223-3p in the injury of ROS induced by Ang II.Material and methodsSerum Ang II levels were examined by ELISA kit. Fibrosis levels of right atrial appendages were determined by Masson’s staining. H9c2 cells tansfected with miR-223-3p mimics were treated with Ang II with or without MCC950 (a potent selective NLRP3 inhibitor). Cell viability was detected by CCK-8 assay. Protein abundance was detected by Western blot. MDA assay and DCFH-DA were used to measured oxidative stress. RT-qPCR was used to assay the expression of miR-223-3p and NLRP3.ResultsTotally, 43 patients enrolled in this study, including 20 patients with persistent (chronic) AF (cAF). Comparing with sinus rhythm (SR) group, we found an enhanced activation of NLRP3 inflammasome which were positively correlated with oxidative stress and serum Ang II level in cAF patients. Ang II induced ROS generation and inhibited the H9c2 cell viability. In addition, overexpression of miR-223-3p functioned as MCC950 which inhibited the expression of NLRP3 inflammasome and partly attenuated the effects of ROS induced by Ang II on H9c2 cell viability. Lastly, we used luciferase assay to confirm NLRP3 as a direct target gene of miR-223-3p.ConclusionsmiR-223-3p has protective effects on oxidative stress induced by Ang II in AF by targeting NLRP3 and could provide a new potential intervention targets for treatment of AF.

scholarly journals Vanillin Prevents Doxorubicin-Induced Apoptosis and Oxidative Stress in Rat H9c2 Cardiomyocytes

Nutrients ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2317 ◽  
Author(s):  
Ivana Sirangelo ◽  
Luigi Sapio ◽  
Angela Ragone ◽  
Silvio Naviglio ◽  
Clara Iannuzzi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Point Of View ◽  
Protective Effects ◽  
H9c2 Cells ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Erk Phosphorylation ◽  
H9c2 Cardiomyocytes ◽  
Induced Apoptosis ◽  
Tumor Types

Doxorubicin (doxo) is an effective anticancer compound in several tumor types. However, as a consequence of oxidative stress induction and ROS overproduction, its high cardiotoxicity demands urgent attention. Vanillin possesses antioxidant, antiproliferative, antidepressant and anti-glycating properties. Therefore, we investigated the potential vanillin protective effects against doxo-induced cardiotoxicity in H9c2 cells. Using multiparametric approach, we demonstrated that vanillin restored both cell viability and damage in response to doxo exposure. Contextually, vanillin decreased sub-G1 appearance and caspase-3 and PARP1 activation, reducing the doxo-related apoptosis induction. From a mechanistic point of view, vanillin hindered doxo-induced ROS accumulation and impaired the ERK phosphorylation. Notably, besides the cardioprotective effects, vanillin did not counteract the doxo effectiveness in osteosarcoma cells. Taken together, our results suggest that vanillin ameliorates doxo-induced toxicity in H9c2 cells, opening new avenues for developing alternative therapeutic approaches to prevent the anthracycline-related cardiotoxicity and to improve the long-term outcome of antineoplastic treatment.

scholarly journals Yangxin granules alleviate doxorubicin-induced cardiotoxicity by suppressing oxidative stress and apoptosis mediated by AKT/GSK3β/β-catenin signaling

2020 ◽  
Vol 48 (8) ◽  
pp. 030006052094516
Author(s):  
Dezhi Ren ◽  
Fang Li ◽  
Qingwen Cao ◽  
An Gao ◽  
Yingna Ai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Molecular Mechanisms ◽  
Inflammatory Factor ◽  
H9c2 Cells ◽  
Akt Inhibitor ◽  
Phosphorylated Akt ◽  
H9c2 Cardiomyocytes ◽  
Clinical Benefits

Background Yangxin granules (YXC), a Chinese herbal medicine, have been confirmed to have clinical benefits in the treatment of heart failure. This study examined the effects and molecular mechanisms of YXC in the treatment of doxorubicin-induced cardiotoxicity in vitro. Methods H9c2 cardiomyocytes were pretreated with YXC (5, 10, or 20 mg/mL) or the AKT inhibitor MK-2206 (50 nM) before doxorubicin treatment (1 µM). Cell apoptosis, viability, inflammatory factor expression (TNF-α, IL-1β, and IL-6), and oxidative stress mediator levels including superoxide dismutase, reactive oxygen species, and malondialdehyde were detected. Results YXC increased the viability of H9c2 cells. In addition, doxorubicin inhibited AKT/GSK3β/β-catenin signaling, whereas YXC increased the expression of phosphorylated AKT and GSK3β, and β-catenin in doxorubicin-treated H9c2 cells. Moreover, T-cell factor/lymphoid enhancer factor signaling downstream of β-catenin was also activated by YXC. YXC pretreatment also inhibited doxorubicin-induced inflammation, oxidative stress, and apoptosis. However, MK-2206 reversed the effects of YXC in doxorubicin-treated H9c2 cells. Conclusions YXC alleviates doxorubicin-induced inflammation, oxidative stress, and apoptosis in H9c2 cells. These effects might be mediated by the AKT/GSK3β/β-catenin signaling pathway. YXC might have preventive effects against doxorubicin-induced heart failure.

scholarly journals Total Flavonoids fromClinopodium chinense(Benth.) O. Ktze Protect against Doxorubicin-Induced CardiotoxicityIn VitroandIn Vivo

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Rong Chang Chen ◽  
Xu Dong Xu ◽  
Xue Zhi Liu ◽  
Gui Bo Sun ◽  
Yin Di Zhu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Tissue ◽  
Tissue Injury ◽  
Apoptotic Cell ◽  
Male Rats ◽  
Ros Generation ◽  
Total Flavonoids ◽  
Protective Effects ◽  
Akt Inhibitor ◽  
H9c2 Cardiomyocytes

Doxorubicin has cardiotoxic effects that limit its clinical benefit in cancer patients. This study aims to investigate the protective effects of the total flavonoids fromClinopodium chinense(Benth.) O. Ktze (TFCC) against doxorubicin- (DOX-) induced cardiotoxicity. Male rats were intraperitoneally injected with a single dose of DOX (3 mg/kg) every 2 days for three injections. Heart samples were collected 2 weeks after the last DOX dose and then analyzed. DOX delayed body and heart growth and caused cardiac tissue injury, oxidative stress, apoptotic damage, mitochondrial dysfunction, and Bcl-2 expression disturbance. Similar experiments in H9C2 cardiomyocytes showed that doxorubicin reduced cell viability, increased ROS generation and DNA fragmentation, disrupted mitochondrial membrane potential, and induced apoptotic cell death. However, TFCC pretreatment suppressed all of these adverse effects of doxorubicin. Signal transduction studies indicated that TFCC suppressed DOX-induced overexpression of p53 and phosphorylation of JNK, p38, and ERK. Studies with LY294002 (a PI3K/AKT inhibitor) demonstrated that the mechanism of TFCC-induced cardioprotection also involves activation of PI3K/AKT. These findings indicated the potential clinical application of TFCC in preventing DOX-induced cardiac oxidative stress.

SGLT1 knockdown prevents glucose fluctuation-induced apoptosis of cardiomyocytes through attenuating oxidative stress and mitochondrial dysfunction

2020 ◽  
Author(s):  
Qian Chai ◽  
Jiajing Miao ◽  
Meili Liu ◽  
Ziying Zhang ◽  
Ziang Meng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Cardiovascular Complications ◽  
H9c2 Cells ◽  
Glucose Fluctuation ◽  
Sodium Glucose Cotransporter ◽  
Antioxidase Activity ◽  
H9c2 Cardiomyocytes ◽  
Underlying Mechanisms ◽  
Induced Apoptosis

Blood glucose fluctuation has been validated to be more detrimental than constant high glucose in the development of cardiovascular complications of diabetes mellitus (DM). Sodium‑glucose cotransporter 2 (SGLT2) inhibitors have been developed as antidiabetic drugs with cardiovascular benefits. However, whether inhibition of SGLT1 protects the diabetic heart remains to be elucidated. The present study investigated the role of SGLT1 in rat H9c2 cardiomyocytes subjected to glucose fluctuation and the underlying mechanisms. The results indicated that SGLT1 knockdown was able to restore cell proliferation and suppress cytotoxicity induced by glucose fluctuation. Glucose fluctuation induced oxidative stress in H9c2 cells, while these changes were reversed effectively by SGLT1 knockdown, as manifested by reduction of intracellular reactive oxygen species and increased antioxidase activity. Further study demonstrated that SGLT1 knockdown attenuated mitochondrial dysfunction in H9c2 cells exposed to glucose fluctuation, including restoration of mitochondrial membrane potential and promotion of mitochondrial fusion. In addition, SGLT1 knockdown downregulated Bax expression, upregulated Bcl-2 expression, and reduced caspase-3 activation in glucose fluctuation-induced H9c2 cells. Taken together, our study reveals that SGLT1 knockdown ameliorates glucose fluctuation-induced cardiomyocyte apoptosis, which might be ascribed to regulation of oxidative stress and mitochondrial dysfunction.

scholarly journals Proanthocyanidins-Mediated Nrf2 Activation Ameliorates Glucocorticoid-Induced Oxidative Stress and Mitochondrial Dysfunction in Osteoblasts

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Liang Chen ◽  
Sun-Li Hu ◽  
Jun Xie ◽  
De-Yi Yan ◽  
She-Ji Weng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Low Dose ◽  
Distal Femur ◽  
Therapeutic Potential ◽  
Protective Effects ◽  
Nrf2 Pathway ◽  
Pathway Activation ◽  
Nrf2 Activation ◽  
Osteoblast Apoptosis

The widespread use of therapeutic glucocorticoids has increased the frequency of glucocorticoid-induced osteoporosis (GIOP). One of the potential pathological processes of GIOP is an increased level of oxidative stress and mitochondrial dysfunction, which eventually leads to osteoblast apoptosis. Proanthocyanidins (PAC) are plant-derived antioxidants that have therapeutic potential against GIOP. In our study, a low dose of PAC was nontoxic to healthy osteoblasts and restored osteogenic function in dexamethasone- (Dex-) treated osteoblasts by suppressing oxidative stress, mitochondrial dysfunction, and apoptosis. Mechanistically, PAC neutralized Dex-induced damage in the osteoblasts by activating the Nrf2 pathway, since silencing Nrf2 partly eliminated the protective effects of PAC. Furthermore, PAC injection restored bone mass and promoted the expression of Nrf2 in the distal femur of Dex-treated osteoporotic rats. In summary, PAC protect osteoblasts against Dex-induced oxidative stress and mitochondrial dysfunction via the Nrf2 pathway activation and may be a promising drug for treating GIOP.

scholarly journals Mitochondria-Targeted Antioxidants for Treatment of Hearing Loss: A Systematic Review

Antioxidants ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 109 ◽  
Author(s):  
Chisato Fujimoto ◽  
Tatsuya Yamasoba
Keyword(s):  
Oxidative Stress ◽  
Hearing Loss ◽  
Mitochondrial Dysfunction ◽  
Cell Lines ◽  
Mitochondrial Gene ◽  
Protective Effects ◽  
Drug Induced ◽  
Age Related ◽  
Cochlear Damage ◽  
Age Related Hearing Loss

Mitochondrial dysfunction is associated with the etiologies of sensorineural hearing loss, such as age-related hearing loss, noise- and ototoxic drug-induced hearing loss, as well as hearing loss due to mitochondrial gene mutation. Mitochondria are the main sources of reactive oxygen species (ROS) and ROS-induced oxidative stress is involved in cochlear damage. Moreover, the release of ROS causes further damage to mitochondrial components. Antioxidants are thought to counteract the deleterious effects of ROS and thus, may be effective for the treatment of oxidative stress-related diseases. The administration of mitochondria-targeted antioxidants is one of the drug delivery systems targeted to mitochondria. Mitochondria-targeted antioxidants are expected to help in the prevention and/or treatment of diseases associated with mitochondrial dysfunction. Of the various mitochondria-targeted antioxidants, the protective effects of MitoQ and SkQR1 against ototoxicity have been previously evaluated in animal models and/or mouse auditory cell lines. MitoQ protects against both gentamicin- and cisplatin-induced ototoxicity. SkQR1 also provides auditory protective effects against gentamicin-induced ototoxicity. On the other hand, decreasing effect of MitoQ on gentamicin-induced cell apoptosis in auditory cell lines has been controversial. No clinical studies have been reported for otoprotection using mitochondrial-targeted antioxidants. High-quality clinical trials are required to reveal the therapeutic effect of mitochondria-targeted antioxidants in terms of otoprotection in patients.

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