H3K9ac modification was involved in doxorubicin induced apoptosis by regulating Pik3ca transcription in H9C2 cells

Fas/Fas ligand (FasL) is implicated in cardiac ischemia/reperfusion injury. However, cardiomyocytes in culture are resistant to FasL-induced apoptosis, suggesting that additional factor(s) are required for FasL-induced apoptosis. Matricellular protein CCN1 has been demonstrated to promote cytotoxicity of FasL in human skin fibroblasts. CCN1 is induced in a variety of cardiac pathologies. We assessed the hypothesis that CCN1 may be involved in the regulation of FasL-induced apoptosis in cardiomyocytes. We found that either FasL or CCN1 did not induce cell death in neonatal rat ventricular cardiomyocytes (NRVM). Interestingly, the combination of FasL+CCN1 generated 2-fold induction of apoptosis (vs. control p<0.001). An integrin-α 6 β 1 -binding defective mutant CCN1, CCN1-DM failed to exert synergy with FasL to induce apoptosis, indicating a critical role of α 6 β 1 . The engagement between CCN1 and α 6 β 1 instigated the elevation of cellular reactive oxygen species (ROS), the activation of mitogen activated protein kinase p38, and followed by the induction of cell surface display of Fas, thereby sensitizing NRVM to FasL-induced apoptosis. Pretreatment of the p38 inhibitor SB202190 abolished the CCN1-induced cell-surface Fas expression and the apoptosis induced by FasL+CCN1. In addition, we tested the interaction between CCN1 and FasL on the cardiomyoblast H9c2 cells. We found that FasL or CCN1 alone did not cause apoptosis in H9c2, and required the combination of FasL+CCN1 to induced apoptosis (vs. control p<0.001) in H9c2 cells, reminiscent of the observation in NRVM. Mechanistically, CCN1 acted through binding to integrin α 6 β 1 , ROS generation, and p38 activation, however, did not increase the expression of cell surface Fas for its synergy with FasL in H9c2 cells. Instead, CCN1 induced Bax translocation to mitochondria, which in turn led to the release of Smac from mitochondria to cytosol. The cytosolic Smac functions to neutralize XIAP. Smac is critical for CCN1 action, because the knockdown of Smac blunted the apoptotic activities of CCN1. In conclusion, CCN1 may play a detrimental role in a stressed heart to both the differentiated cardiomyocytes and the proliferative cardioblasts through distinct signaling mechanisms.

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Puerarin attenuates the daunorubicin-induced apoptosis of H9c2 cells by activating the PI3K/Akt signaling pathway via the inhibition of Ca2+ influx

International Journal of Molecular Medicine ◽

10.3892/ijmm.2017.3186 ◽

2017 ◽

Cited By ~ 1

Author(s):

Weihua Li ◽

Min Lu ◽

Yanhong Zhang ◽

Danqin Xia ◽

Zebin Chen ◽

...

Keyword(s):

Signaling Pathway ◽

Akt Signaling ◽

H9c2 Cells ◽

Akt Signaling Pathway ◽

Induced Apoptosis

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Cardioprotective effect of KR-33889, a novel PARP inhibitor, against oxidative stress-induced apoptosis in H9c2 cells and isolated rat hearts

Archives of Pharmacal Research ◽

10.1007/s12272-017-0912-3 ◽

2017 ◽

Vol 40 (5) ◽

pp. 640-654 ◽

Cited By ~ 9

Author(s):

Eun-Seok Park ◽

Do-Hyun Kang ◽

Jun Chul Kang ◽

Yong Chang Jang ◽

Min-Ju Lee ◽

...

Keyword(s):

Oxidative Stress ◽

Parp Inhibitor ◽

Cardioprotective Effect ◽

H9c2 Cells ◽

Rat Hearts ◽

Induced Apoptosis ◽

Isolated Rat

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Swainsonine protects H9c2 cells against lipopolysaccharide-induced apoptosis and inflammatory injury via down-regulating miR-429

Cell Cycle ◽

10.1080/15384101.2019.1706902 ◽

2019 ◽

Vol 19 (2) ◽

pp. 207-217

Author(s):

Hongyan Lv ◽

Su Zhang ◽

Xiaohong Hao

Keyword(s):

H9c2 Cells ◽

Inflammatory Injury ◽

Induced Apoptosis

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Effects of Four Compounds from Gentianella acuta (Michx.) Hulten on Hydrogen Peroxide-Induced Injury in H9c2 Cells

BioMed Research International ◽

10.1155/2019/2692970 ◽

2019 ◽

Vol 2019 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Kai Ren ◽

He Su ◽

Li-juan Lv ◽

Le-tai Yi ◽

Xue Gong ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Protein Expression ◽

Treated Group ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Protective Effects ◽

H9c2 Cells ◽

Mtt Method ◽

Bioassay Guided Fractionation ◽

Induced Apoptosis

In previous studies, Gentianella acuta (Michx.) Hulten was reported to contain xanthones, iridoids, terpenoids, and sterols and is mainly used to cure hepatitis, jaundice, fever, headache, and angina pectoris. In this study, we used bioassay guided fractionation to identify compounds from G. acuta and investigated their activity against hydrogen peroxide (H2O2)-induced apoptosis of H9c2 cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutamate-cysteine ligase catalytic (GCLC) expression were assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was evaluated using western blot. The results showed that all four compounds had protective effects on H9c2 cells. The transcription levels of HO-1 and GCLC significantly increased in H9c2 cells pretreated with norswertianolin (1), swetrianolin (2), demethylbellidifolin (3), and bellidifolin (4). However, compared to the model group, the transcription levels of Nrf2 were not enhanced by pretreatment with compounds 1, 2, and 4. The protein expression levels of HO-1 and GCLC in H9c2 cells were greater than that in the H2O2-treated group, and the expression of Nrf2 was not significantly changed except by swetrianolin treatment; inhibitors can reverse the protective effect by ZnPP (15 μM), BSO (10 μM), and brusatol (10 μM). The results indicated that the four compounds isolated from G. acuta inhibited the oxidative injury induced by H2O2 by activating the Nrf2/ARE pathway in H9c2 cells and provide evidence that G. acuta may be a potential therapeutic agent for the treatment of cardiovascular diseases.

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Exosomes derived from cardiac progenitor cells attenuate CVB3-induced apoptosis via abrogating the proliferation of CVB3 and modulating the mTOR signaling pathways

Cell Death and Disease ◽

10.1038/s41419-019-1910-9 ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 2

Author(s):

Xin Li ◽

Zuocheng Yang ◽

Wenyuan Nie ◽

Jie Jiang ◽

Shentang Li ◽

...

Keyword(s):

Signaling Pathways ◽

Progenitor Cells ◽

Viral Myocarditis ◽

Specific Treatment ◽

Mtor Signaling ◽

Cardiac Progenitor Cells ◽

H9c2 Cells ◽

Cvb3 Infection ◽

Infected Cells ◽

Induced Apoptosis

Abstract Viral myocarditis is potentially fatal and lacking a specific treatment. Exosomes secreted by cardiac progenitor cells (CPCs) have emerged as a promising tool for cardioprotection and repair. In this study, we investigated whether CPCs-derived exosomes (CPCs-Ex) could utilize the mTOR signal pathway to reduce the apoptosis in viral myocarditis. In vitro, exosomes were, respectively, added to H9C2 cells after CVB3 infection to detect the anti-apoptosis effect of CPCs-Ex. Compared with the controls, the apoptosis rate was reduced, accompanied with the depressed expression of viral capsid protein 1 (VP1) and pro-apoptosis factors of Bim/caspase families. Meanwhile, the phosphorylation of Akt, mTOR, and p70S6K were promoted, but that of 4EBP1 was suppressed. In vivo, the results of apoptosis, expression of CVB3 and pro-apoptosis factors, and phosphorylation of Akt/mTOR factors of CVB3-infected cardiomyocytes were consistent with that of vitro. Following that, we use Rapamycin and MK-2206 to inhibit the Akt/mTOR signaling pathway, meanwhile, Rattus 4EBP1, p70S6K, Akt1 and Akt2 were transfected to H9C2 cells to establish the stably transfected cell lines. In the group with Rapamycin or MK-2206 pretreatment, CPCs-Ex also could decrease the apoptosis of H9C2 cells and expression of CVB3 mRNA, followed by decreased expression of apoptosis factors. In Akt2, p70S6K and 4EBP1 overexpression groups, CPCs-Ex promoted CVB3-induced apoptosis, VP1 expression and cleavage of caspase-3. Our results therefore identify CPCs-Ex exerts an anti-apoptosis effect in CVB3-infected cells by abrogating the proliferation of CVB3 and modulating the mTOR signaling pathways as well as the expression of Bcl-2 and caspase families. Viral myocarditis, mainly caused by CVB3 infection, is lacking a specific treatment. Our study identified an anti-apoptosis role of CPCs-Ex in CVB3-infected cells and rats, which shown that CPCs-Ex may be an effective tool to treat viral myocarditis. We believe that with more in-depth research on the functionality of CPCs-Ex, there will be a breakthrough in the treatment of viral myocarditis.

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Hypaconitine protects H9c2 cells from oxidative stress-induced apoptosis

Journal of Medicinal Plants Research ◽

10.5897/jmpr11.1467 ◽

2012 ◽

Vol 6 (5) ◽

Author(s):

Zhi-Hui Li

Keyword(s):

Oxidative Stress ◽

H9c2 Cells ◽

Induced Apoptosis

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Iron-Overload Induces Apoptosis in Cardiomyocytes and Hepatocytes Via Mitochondrial/Caspase-3 Pathways.

Blood ◽

10.1182/blood.v112.11.1872.1872 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1872-1872

Author(s):

Mo Yang ◽

Shing Chan ◽

Yiu Fai Cheung ◽

Shau Yin Ha ◽

Godfrey ChiFung Chan

Keyword(s):

Iron Overload ◽

Protective Effect ◽

Cell Viability ◽

Caspase 3 ◽

Annexin V ◽

Apoptotic Cells ◽

H9c2 Cells ◽

Plot Analysis ◽

Iron Treatment ◽

Induced Apoptosis

Abstract Cardiomyopathy and liver damage due to iron-overload are the major complications in patients with beta-thalassaemia major. Iron-overload may induce apoptosis in cardiomyocytes and hepatic cells, and that TPO may exert protective effect on apoptosis of cardiomyocytes (Circulation, 2006). In this study, we demonstrated firstly that iron induced apoptosis in cardiomyocytes. Using H9C2 cells, we have shown that iron reduced cell viability in a dose-dependent manner (0.003–3 mM) (n=6). By annexin V and PI staining, apoptotic cells were found to be significantly increased after iron treatment (0.3 mM, 72 hrs) (n=6). The expression of active caspase-3 was significantly increased in iron-treated cells. Furthermore, iron treatment increased the proportion of cells containing JC-1 monomers, indicating a trend in the drop of mitochondrial membrane potential (n=6). Secondly, we found that TPO exerted cardio-protective effect on iron-induced apoptosis. H9C2 cells were cultured in the presence of iron (0.3 mM) with or without TPO (5, 10, 20, 50, 100 ng/mL, 72 hrs). The cell viability was significantly increased with the treatment of TPO at 50 ng/mL and 100 ng/mL (n=4). Dot-plot analysis of annexin V/PI staining demonstrated that TPO (50 ng/mL) significantly reduced the population of apoptotic cells (n=6). Incubation with TPO also decreased the iron-induced caspase-3 expression (n=6). Flow cytometric dot-plot analysis of H9C2 cells also showed trends of amelioration of the increase in JC-1 monomers in the iron plus TPO group (n=6). The population of phospho-Akt and Erk1/2 were also significantly increased after treatment by TPO (P<0.05, n=4). Human liver cell line MIHA was also used as a cell model. We showed that iron-overload reduced cell viability in a dose-dependent manner (0.0375–0.6 mM) (n=7). By annexin V and PI staining, apoptotic cells were found to be significantly increased after iron treatment (0.15–0.6 mM) for 72 hrs (n=7). The expression of active caspase-3 was also significantly increased in iron-treated cells (n=5). We also found that TPO exerted proliferation effect on MIHA cell by activation of phospho-Akt. However, MIHA cells were cultured in the presence of iron (0.3 mM) with TPO (50 ng/mL, 72 hrs). The cell viability was not significantly increased with the treatment of TPO (n=5). Dot-plot analysis of annexin V/PI staining did not demonstrated that TPO reduced the population of apoptotic cells induced by iron-overload (n=5). Also, incubation with TPO did not decrease the iron-induced caspase-3 expression in these cells (n=5). Our findings suggest that iron-overload induces apoptosis in cardiomyocytes and hepatocytes via mitochondrial/caspase-3 pathways and that TPO might exert a protective effect on iron-overload induced apoptosis via the activation of Akt and Erk1/2 pathways in cardiomyocytes.

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