Exendin-4 protects adipose-derived mesenchymal stem cells from apoptosis induced by hydrogen peroxide through the PI3K/Akt–Sfrp2 pathways

• Published in: Free radical biology & medicine Vol. 77; pp. 363 - 375
• Main Authors: Zhou, Hao, Yang, Junjie, Xin, Ting, Li, Dandan, Guo, Jun, Hu, Shunyin, Zhou, Shanshan, Zhang, Tao, Zhang, Ying, Han, Tianwen, Chen, Yundai
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2014
• Subjects: ADMSCs; Animals; Apoptosis; Apoptosis - drug effects; Cell Survival; Drug Evaluation, Preclinical; Exendin-4; Free radicals; Glucagon-Like Peptide-1 Receptor; Hydrogen Peroxide - pharmacology; Membrane Proteins - metabolism; Mesenchymal Stromal Cells - drug effects; Mesenchymal Stromal Cells - physiology; Mitochondria-dependent cell apoptosis; Oxidative Stress; Peptides - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; PI3K/Akt pathway; Proto-Oncogene Proteins c-akt - metabolism; Rats, Sprague-Dawley; Receptors, Glucagon - metabolism; Sfrp2; Signal Transduction; Venoms - pharmacology; Sfrp2; PI3K/Akt pathway; Free radicals; ADMSCs; Mitochondria-dependent cell apoptosis; Exendin-4; Apoptosis
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2014.09.033

Adipose-derived mesenchymal stem cells (ADMSCs)-based therapy is a promising modality for the treatment of myocardial infarction in the future. However, the majority of transplanted cells are readily lost after transplantation because of hypoxia and oxidative stress. An efficient means to enhance the ability of ADMSCs to survive under pathologic conditions is required. In our study, we explored the effects of exendin-4 (Ex-4) on ADMSCs apoptosis in vitro induced by hydrogen peroxide, focusing in particular on mitochondrial apoptotic pathways and PI3K/Akt–secreted frizzled-related protein 2 (Sfrp2) survival signaling. We demonstrated that ADMSCs subjected to H2O2 for 12h exhibited impaired mitochondrial function and higher apoptotic rate. However, Ex-4 (1–20nM) preconditioning for 12h could protect ADMSCs against H2O2-mediated apoptosis in a dose-dependent manner. Furthermore, Ex-4 pretreatment upregulated the levels of superoxide dismutase and glutathione as well as downregulating the production of reactive oxygen species and malondialdehyde. Western blots revealed that increased antiapoptotic proteins Bcl-2 and c-IAP1/2 as well as decreased proapoptotic proteins Bax and cytochrome c appeared in ADMSCs with Ex-4 incubation, which inhibited the caspase-9-involved mitochondrial apoptosis pathways with evidence showing inactivation of caspase-9/3 and preservation of mitochondrial membrane potential. Furthermore, we illustrated that Ex-4 enhanced Akt phosphorylation, which increased the expression of Sfrp2. Notably, blockade of the PI3K/Akt pathway or knockdown of Sfrp2 with siRNA obviously abolished the protective effects of Ex-4 on mitochondrial function and ADMSCs apoptosis under H2O2. In summary, this study confirmed that H2O2 induced ADMSCs apoptosis through mitochondria-dependent cell death pathways, and Ex-4 preconditioning may reduce such apoptosis of ADMSCs through the PI3K/Akt–Sfrp2 pathways.
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•Exogenous hydrogen peroxide (H2O2) could induce ADMSC apoptosis through the mitochondrial death pathway.•Exendin-4 preconditioning could dose-dependently protect ADMSCs against H2O2-mediated apoptosis via preservation of mitochondrial function.•Exendin-4 enhanced Akt phosphorylation, which increased the expression of secreted frizzled-related protein 2 (Sfrp2) in ADMSCs.•Blockade of PI3K/Akt pathway or Sfrp2 knockdown with siRNA abolished the protective effects of Ex-4 on mitochondrial function and ADMSC apoptosis under H2O2.