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Exendin-4 protects bone marrow-derived mesenchymal stem cells against oxygen/glucose and serum deprivation-induced apoptosis through the activation of the cAMP/PKA signaling pathway and the attenuation of ER stress

  • Authors:
    • Jieqiong He
    • Chao Wang
    • Yunpeng Sun
    • Bo Lu
    • Jinjin Cui
    • Nana Dong
    • Maomao Zhang
    • Youbing Liu
    • Bo Yu
  • View Affiliations / Copyright

    Affiliations: The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang, P.R. China, Department of Cardiology, The First Hospital of Qiqihar, Qiqihar, Heilongjiang, P.R. China
    Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 889-900
    |
    Published online on: February 29, 2016
       https://doi.org/10.3892/ijmm.2016.2509
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Abstract

Exendin-4 (ex-4) is a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist which exerts beneficial effects on glycemic control and promotes cell viability. In the present study, we investigated the anti-apoptotic effects of ex-4, as well as the potential mechanisms responsible for these effects in rat bone marrow-derived mesenchymal stem cells (BM-MSCs) under conditions of oxygen, glucose and serum deprivation (OGD). The apoptosis of the MSCs was induced by subjecting the cells to OGD conditions for 4 h and was detected by Annexin V/PI and Hoechst 33258 staining. The MSCs were pre-conditioned with ex-4 for 12 h prior to being subjected to OGD conditions, and the expression levels of an apoptotic marker (cleaved caspase-3), endoplasmic reticulum (ER) stress markers [phosphorylated (p-)protein kinase RNA-like endoplasmic reticulum kinase (PERK), PERK, binding immunoglobulin protein (BIP), activating transcription factor 4 (ATF-4) and C/EBP homologous protein (CHOP)], as well as those of a survival marker (Bcl-2) were measured by western blot analysis. Furthermore, the mRNA levels of ATF-4 and CHOP were determined by RT-qPCR. ELISA was used to examine the activity of intracellular cAMP. Moreover, the GLP-1R antagonist, exendin9-39 (ex9-39), the protein kinase A (PKA) inhibitor, H89, and small interfering RNA (siRNA) targeting rat ATF-4 and CHOP were co-incubated with the MSCs. The apoptotic rate was markedly diminished following pre-conditioning with ex-4 in a dose‑dependent manner (P<0.05). The ER stress markers, p-PERK, BIP, ATF-4 and CHOP, were upregulated in the cells subjected to OGD conditions. Ex-4 pre-conditioning significantly decreased the mRNA and protein levels of ATF-4 and CHOP (P<0.05), and increased the activity of intracellular cAMP (P<0.05). Furthermore, the anti-apoptotic effects of ex-4 were almost reversed by treatment with either H89 or ex9-39 (P<0.05); transfection with siRNA-CHOP significantly reduced the apoptotic rate of the MSCs and did not impair the cytoprotective effects of ex-4. Taken together, these findings suggest that ex-4 protects rat BM-MSCs from OGD-induced apoptosis through the activation of the PKA/cAMP pathway and the attenuation of the ER stress signaling pathway. Ex-4 may thus prove to be a therapeutic agent with the potential to improve the viability of MSCs in the ischemic milieu, and consequently, to optimize the therapeutic effects of MSC therapy in acute myocardial infarction.
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Copy and paste a formatted citation
Spandidos Publications style
He J, Wang C, Sun Y, Lu B, Cui J, Dong N, Zhang M, Liu Y and Yu B: Exendin-4 protects bone marrow-derived mesenchymal stem cells against oxygen/glucose and serum deprivation-induced apoptosis through the activation of the cAMP/PKA signaling pathway and the attenuation of ER stress. Int J Mol Med 37: 889-900, 2016.
APA
He, J., Wang, C., Sun, Y., Lu, B., Cui, J., Dong, N. ... Yu, B. (2016). Exendin-4 protects bone marrow-derived mesenchymal stem cells against oxygen/glucose and serum deprivation-induced apoptosis through the activation of the cAMP/PKA signaling pathway and the attenuation of ER stress. International Journal of Molecular Medicine, 37, 889-900. https://doi.org/10.3892/ijmm.2016.2509
MLA
He, J., Wang, C., Sun, Y., Lu, B., Cui, J., Dong, N., Zhang, M., Liu, Y., Yu, B."Exendin-4 protects bone marrow-derived mesenchymal stem cells against oxygen/glucose and serum deprivation-induced apoptosis through the activation of the cAMP/PKA signaling pathway and the attenuation of ER stress". International Journal of Molecular Medicine 37.4 (2016): 889-900.
Chicago
He, J., Wang, C., Sun, Y., Lu, B., Cui, J., Dong, N., Zhang, M., Liu, Y., Yu, B."Exendin-4 protects bone marrow-derived mesenchymal stem cells against oxygen/glucose and serum deprivation-induced apoptosis through the activation of the cAMP/PKA signaling pathway and the attenuation of ER stress". International Journal of Molecular Medicine 37, no. 4 (2016): 889-900. https://doi.org/10.3892/ijmm.2016.2509
Copy and paste a formatted citation
x
Spandidos Publications style
He J, Wang C, Sun Y, Lu B, Cui J, Dong N, Zhang M, Liu Y and Yu B: Exendin-4 protects bone marrow-derived mesenchymal stem cells against oxygen/glucose and serum deprivation-induced apoptosis through the activation of the cAMP/PKA signaling pathway and the attenuation of ER stress. Int J Mol Med 37: 889-900, 2016.
APA
He, J., Wang, C., Sun, Y., Lu, B., Cui, J., Dong, N. ... Yu, B. (2016). Exendin-4 protects bone marrow-derived mesenchymal stem cells against oxygen/glucose and serum deprivation-induced apoptosis through the activation of the cAMP/PKA signaling pathway and the attenuation of ER stress. International Journal of Molecular Medicine, 37, 889-900. https://doi.org/10.3892/ijmm.2016.2509
MLA
He, J., Wang, C., Sun, Y., Lu, B., Cui, J., Dong, N., Zhang, M., Liu, Y., Yu, B."Exendin-4 protects bone marrow-derived mesenchymal stem cells against oxygen/glucose and serum deprivation-induced apoptosis through the activation of the cAMP/PKA signaling pathway and the attenuation of ER stress". International Journal of Molecular Medicine 37.4 (2016): 889-900.
Chicago
He, J., Wang, C., Sun, Y., Lu, B., Cui, J., Dong, N., Zhang, M., Liu, Y., Yu, B."Exendin-4 protects bone marrow-derived mesenchymal stem cells against oxygen/glucose and serum deprivation-induced apoptosis through the activation of the cAMP/PKA signaling pathway and the attenuation of ER stress". International Journal of Molecular Medicine 37, no. 4 (2016): 889-900. https://doi.org/10.3892/ijmm.2016.2509
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