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Neuregulin-1 suppresses cardiomyocyte apoptosis by activating PI3K/Akt and inhibiting mitochondrial permeability transition pore

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Abstract

Neuregulin-1 (NRG-1) has been shown to attenuate cardiomyocyte apoptosis but the underlying signaling mechanism remains elusive. In this study, we focused on mitochondrial permeability transition pore (mPTP) opening and PI3K/Akt pathway to investigate the effects of NRG-1 on oxidative stress-induced apoptosis of cardiomyocyte. Human cardiac myocytes and neonatal rat cardiac myocytes were exposed to hydrogen peroxide with or without pre-treatment with recombinant human neuregulin-1 (rhNRG-1). Cell apoptosis and mPTP opening were assayed by flow cytometry and confocal microscopy. The activation of Akt was detected by western blot analysis. The results showed that H2O2 induced cardiomyocyte apoptosis and activated mPTP. rhNRG-1 inhibited mPTP and activated Akt in the presence of H2O2, and further protected the cells from H2O2-induced apoptosis. However, rhNRG-1 failed to inhibit mPTP opening and cell apoptosis in the presence of PI3K inhibitor LY294002. Taken together, these findings suggest that NRG-1 activates PI3K/Akt signaling and inhibits mPTP opening, and downstream apoptotic events in cardiac myocytes subjected to oxidative stress.

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Acknowledgments

This study was supported by Beijing Natural Science Foundation (No. 7102043). We thank Zensun Sci & Tech Ltd. (Shanghai, China) for providing neuregulin-1.

Conflict of interest

The authors declared no conflict of interest.

Author information

Authors and Affiliations

  1. Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

    Bingzhang Jie, Xiaoxia Zhang & Xuesi Wu

  2. Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, 100029, China

    Yi Xin

  3. Joint Laboratory of Apoptosis and Cancer Biology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China

    Yong Liu

  4. Department of Cardiology, The Affiliated Hospital of Medical College of Qingdao University, Qingdao, 266000, China

    Yongfang Guo

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  1. Bingzhang Jie
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  2. Xiaoxia Zhang
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  3. Xuesi Wu
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  4. Yi Xin
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  5. Yong Liu
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Correspondence to Xuesi Wu.

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11010_2012_1395_MOESM1_ESM.tif

Figure S1 The effect of rhNRG-1 on mitochondrial dysfunction in HCM. Cells were treated with 200 μM H2O2 for 3 h in the presence or absence of 200 ng/mL rhNRG-1 or 50 μM LY294002 as indicated, and then incubated with calcein-AM alone and with calcein-AM in the presence of CoCl2 and analyzed by confocal microscopy. The change in calcein-AM fluorescence intensity between control cells and stimulated cells indicated the effect of rhNRG-1 on mPTP. Each experiment was repeated at least three times with similar results. Bars, 10 μm. 1 (TIFF 9671 kb)

11010_2012_1395_MOESM2_ESM.tif

Figure S2 The effect of rhNRG-1 on the activation of Bax in HCM. Cells were treated with 200 μM H2O2 for 3 h in the presence or absence of 200 ng/mL rhNRG-1 or 50 μM LY294002 as indicated. Double immunofluorescent staining of cells using anti-Bax mAb and MitoTracker Red CMXRos showed that in control cells extremely weak Bax staining was detected. At 3 h post- H2O2 treatment, Bax staining became stronger and revealed significant co-localization with the mitochondrial marker. Note also the mitochondrial fragmentation in H2O2 treatment cells compared to the controls. Each experiment was repeated at least three times with similar results. Bars, 10 μm. 2 (TIFF 10293 kb)

11010_2012_1395_MOESM3_ESM.tif

Figure S3 The effect of rhNRG-1 on the release of cytochrome c from the mitochondria in HCM. Cells were treated as indicated. Double immunofluorescent staining of cells using anti-cytochrome c mAb and MitoTracker Red CMXRos showed that in control cells extremely weak cytochrome c staining was detected. At 3 h post- H2O2 treatment, cytochrome c fluorescent staining was diffuse in H2O2 treatment cells. Note also the mitochondrial fragmentation in H2O2 treatment cells compared to the controls. Each experiment was repeated at least three times with similar results. Bars, 10 μm. (TIFF 12406 kb)

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Jie, B., Zhang, X., Wu, X. et al. Neuregulin-1 suppresses cardiomyocyte apoptosis by activating PI3K/Akt and inhibiting mitochondrial permeability transition pore. Mol Cell Biochem 370, 35–43 (2012). https://doi.org/10.1007/s11010-012-1395-7

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  • DOI: https://doi.org/10.1007/s11010-012-1395-7

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