The protection effects of survivin in the cell model of CVB3-induced viral myocarditis

Wu, Rongzhou; Wu, Tingting; Li, Ping; Wang, Qiaoyu; Shi, Youyang; Zhan, Yi; Zhang, Songyue; Xia, Tianhe; Wang, Zhenquan; Lv, Haitao

doi:10.1007/s00380-020-01607-y

Cited by 7 publications

(5 citation statements)

References 36 publications

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“…As contradictory results have also been published concerning the type of cell death caused by CVB3, we wanted to investigate the mode of cell death in CVB3-infected HeLa cells, HL-1 cells, H9c2 cells and iCell ® Cardiomyocytes. Among the different modes of cell death, apoptosis and pyroptosis are discussed in the context of CVB3-induced myocarditis [ 8 , 9 , 10 , 16 , 24 ]. To evaluate whether caspase-1 or caspase-3 are activated upon CVB3 infection, we performed Western blot analyses.…”

Section: Resultsmentioning

confidence: 99%

“…Bozym et al found that polarized intestinal epithelial cells (Caco-2 cells) perish by necrosis upon CVB3 infection [ 7 ]. In contrast, others describe cardiomyocyte apoptosis in the heart of CVB3-infected mice and in CVB3-infected HeLa and H9c2 cells [ 3 , 5 , 8 , 9 , 10 ]. Recently, the role of programmed necrosis (necroptosis) was discussed in a mouse model of viral myocarditis [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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In Vitro Model Systems of Coxsackievirus B3-Induced Myocarditis: Comparison of Commonly Used Cell Lines and Characterization of CVB3-Infected iCell® Cardiomyocytes

Kraft¹,

Sauter²,

Seebohm

et al. 2021

Viruses

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Coxsackievirus B3 (CVB3) belongs to the enteroviruses, which are a well-known cause of acute and chronic myocarditis, primarily infecting cardiac myocytes. As primary human cardiomyocytes are difficult to obtain, viral myocarditis is quite frequently studied in vitro in different non-cardiac and cardiac-like cell lines. Recently, cardiomyocytes that have been differentiated from human-induced pluripotent stem cells have been described as a new model system to study CVB3 infection. Here, we compared iCell® Cardiomyocytes with other cell lines that are commonly used to study CVB3 infection regarding their susceptibility and patterns of infection and the mode of cell death. iCell® Cardiomyocytes, HeLa cells, HL-1 cells and H9c2 cells were infected with CVB3 (Nancy strain). The viral load, CVB3 RNA genome localization, VP1 expression (including the intracellular localization), cellular morphology and the expression of cell death markers were compared. The various cell lines clearly differed in their permissiveness to CVB3 infection, patterns of infection, viral load, and mode of cell death. When studying the mode of cell death of CVB3-infected iCell® Cardiomyocytes in more detail, especially regarding the necroptosis key players RIPK1 and RIPK3, we found that RIPK1 is cleaved during CVB3 infection. iCell® Cardiomyocytes represent well the natural host of CVB3 in the heart and are thus the most appropriate model system to study molecular mechanisms of CVB3-induced myocarditis in vitro. Doubts are raised about the suitability of commonly used cell lines such as HeLa cells, HL-1 cells and H9c2 cells to evaluate molecular pathways and processes occurring in vivo in enteroviral myocarditis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Vitro Model Systems of Coxsackievirus B3-Induced Myocarditis: Comparison of Commonly Used Cell Lines and Characterization of CVB3-Infected iCell® Cardiomyocytes

Kraft¹,

Sauter²,

Seebohm

et al. 2021

Viruses

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“…In a study of myocardial ischemia, it was also evident that the expression of survivin protein in cardiomyocytes increased significantly after ischemia-reperfusion injury ( Yang et al, 2015 ). In our previous studies, we noticed that survivin overexpressed in viral myocarditis and the up-regulation of survivin negatively correlated with the expression of Cleaved Caspase-3, suggesting that survivin may protect cardiomyocytes from CVB3- induced apoptosis ( Li et al, 2019 ; Wu et al, 2020 ; Yu et al, 2015 ). Martínez-García et al reported that T21 inhibited STAT3 phosphorylation in lung cancer, which reducing the gene expression of survivin ( Martinez-Garcia et al, 2019 ).…”

Section: Discussionmentioning

confidence: 96%

STAT3 Suppresses Cardiomyocytes Apoptosis in CVB3-Induced Myocarditis Via Survivin

Wang

Zhu

et al. 2021

Front. Pharmacol.

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Background: Viral myocarditis (VMC) is a common inflammatory cardiovascular disease with unclear mechanisms, which mainly affects children and adolescents. Apoptosis is the key to CVB3-induced myocarditis, and blocking this process may be beneficial to the therapy of VMC. Hence, this study aimed to explore the protective function of STAT3 on cardiomyocyte apoptosis of VMC and its underlying mechanisms.Methods and Results: In this research, we confirmed that STAT3 was significantly activated in both animal and cell models of VMC. To further clarify what role did STAT3 play in VMC, AG490, an inhibitor of STAT3, was used to suppress p-STAT3. Our results demonstrated that decreased expression of p-STAT3 caused by AG490 significantly aggravated severity of VMC with elevated myocardial inflammation, deteriorative ventricular systolic function and increased mortality. It suggested that STAT3 plays a protective role in VMC. To further identify the anti-apoptosis impact that activated STAT3 made, we constructed lentivirus to regulate the expression of STAT3 in NMCs. We found that up-regulated activated STAT3 attenuated cardiomyocyte apoptosis, but down-regulated one aggravated that, which verified activated STAT3 played an anti-apoptosis role in VMC. Following that, we explored what elements are involved in the anti-apoptotic mechanism of activated STAT3 by using survivin inhibitor YM155. The result showed the anti-apoptotic effect of activated STAT3 does not work in the case of survivin inhibition.Conclusion: Our findings demonstrated STAT3 by targeting survivin alleviated cardiomyocyte apoptosis in CVB3-induced myocarditis.

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“…Previous report illustrated that GBMs with high expression of Survivin exhibited radioresistance [31]. Some scholars believed that Survivin could restrain the activation of caspase-3, caspase-7, and caspase-9 and weaken apoptosis mediated by them [32][33][34]. As expected, in the present study, except for the observed promotive effect on cell apoptosis and cell cycle blockage of GBM tumors, we found that radiation, resveratrol, or cotreatment also effectively suppressed Cyclin D1, C-myc, and Survivin levels as well as the ratios of p-STAT3 (ser 727)/STAT3, p-STAT3 (tyr 705)/STAT3, and p-AKT/ AKT and upregulated Bad, Cleaved Caspase-9, p-p53, and p-p21 levels in GBM tissues, suggesting that resveratrol triggered apoptosis by downregulating the AKT/ STAT3 signaling pathway, thereby enhancing the effect of radiotherapy.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Enhances the Radiosensitivity by Inducing DNA Damage and Antitumor Immunity in a Glioblastoma Rat Model under 3 T MRI Monitoring

Qian

Mao

et al. 2022

Journal of Oncology

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Glioblastoma (GBM) is the most common intracranial tumor with characteristic of malignancy. Resveratrol, a natural originated polyphenolic compound, has been reported to act as a potential radiosensitizer in cancer therapy. Magnetic resonance imaging (MRI) is the first choice for the diagnosis, pathological grading, and efficacy evaluation of GBM. In this study, MRI was applied to observe whether resveratrol could intensify the anti-GBM tumor effect by enhancing antitumor immunity during radiotherapy. We established an intracranial C6 GBM model in SD rats, treated with radiation and resveratrol. The increased body weight, the inhibition on mortality, and tumor volume in radiated- GBM rats were further enhanced by resveratrol addition, while the pathological damage of brain was alleviated. The modulation of radiation on inflammation, cell cycle, and apoptosis was strengthened by resveratrol; and Ki-67, PD-L1, and cell cycle- and apoptosis-related protein expressions were also improved by cotreatment. Besides, cotreatment attenuated DNA damage and induced G0/G1-phase cell arrest of GBM rats, accompanied with the changed expression of ATM-AKT-STAT3 pathway-related proteins. Moreover, the percentages of CD3+CD8+T cells and IFN-γ+CD8+T cells were enhanced, while (CD4+CD25+Foxp3)/CD4+T cells were decreased by radiation or resveratrol, which was strengthened by cotreatment. The modulation effect of cotreatment on CD3, Foxp3, and IFN-γ levels was also stronger than radiation or resveratrol alone. To conclude, resveratrol enhanced the effect of radiotherapy by inducing DNA damage and antitumor immunity in the intracranial C6 GBM.

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The protection effects of survivin in the cell model of CVB3-induced viral myocarditis

Cited by 7 publications

References 36 publications

In Vitro Model Systems of Coxsackievirus B3-Induced Myocarditis: Comparison of Commonly Used Cell Lines and Characterization of CVB3-Infected iCell® Cardiomyocytes

In Vitro Model Systems of Coxsackievirus B3-Induced Myocarditis: Comparison of Commonly Used Cell Lines and Characterization of CVB3-Infected iCell® Cardiomyocytes

STAT3 Suppresses Cardiomyocytes Apoptosis in CVB3-Induced Myocarditis Via Survivin

Resveratrol Enhances the Radiosensitivity by Inducing DNA Damage and Antitumor Immunity in a Glioblastoma Rat Model under 3 T MRI Monitoring

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