title: Exendin-4 protects adipose-derived mesenchymal stem cells from apoptosis induced by hydrogen peroxide through the PI3K/Akt-Sfrp2 pathways.
abstract: 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 (1-20 nM) 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.
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Xin
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Shunyin
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Tianwen
authors.initials: T
authors.lastname: Han
authors.affiliation: Department of Cardiology, Chinese PLA General Hospital, Beijing 100853, China. Electronic address: yundaic@163.com.
authors.forename: Yundai
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival; D004353:Drug Evaluation, Preclinical; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008565:Membrane Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress; D010455:Peptides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000378:metabolism; D015398:Signal Transduction; D014688:Venoms / Q000494:pharmacology*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D006861:Hydrogen Peroxide; D008565:Membrane Proteins; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018027:Receptors, Glucagon; D014688:Venoms; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins
keywords: ADMSCs; Apoptosis; Exendin-4; Free radicals; Mitochondria-dependent cell apoptosis; PI3K/Akt pathway; Sfrp2