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.