Glucagon Like Peptide-1 Counteracts Occupational Stress Dependent Apoptosis of Human Cardiac Progenitor Cells by Inhibiting the Activation of the c-Jun N-terminal Protein Kinase Signaling Pathway
Increased apoptosis of cardiac progenitor cells (CPCs) has been proposed as a mechanism of myocardial damage and dysfunction. Glucagon-like peptide-1 (GLP-1) has been shown to improve heart
recovery and function after ischemia and to promote cell survival. The protective effects of GLP-1
on oxidative stress-induced apoptosis were investigated in human CPCs isolated from human heart
biopsies. Mesenchymal-type cells were isolated from human heart biopsies, exhibited the marker
profile of CPCs, differentiated toward the myocardiocyte, adipocyte, chondrocyte, and osteocyte
lineages under appropriate culture conditions, and expressed functional GLP-1 receptors. CPCs
were incubated with GLP-1 with or without hydrogen peroxide (H2O2). Phospho- and total proteins
were detected by immunoblotting and immunofluorescence analysis. Gene was evaluated by quantitative RT-PCR. The role of the canonical GLP-1 receptor was assessed by using the
receptor antagonist exendin(9 –39) and receptor-specific silencer small interfering RNAs. Cell apoptosis was quantified by an ELISA assay and by flow cytometry-detected Annexin V. Exposure of
CPCs to H2O2 induced a 2-fold increase in cell apoptosis, mediated by activation of the c-Jun
N-terminal protein kinase (JNK) pathway. Preincubation of CPCs with GLP-1 avoided H2O2-triggered JNK phosphorylation and nuclear localization, and protected CPCs from apoptosis. The GLP-1
effects were markedly reduced by coincubation with the receptor antagonist exendin(9 –39), small
interfering RNA-mediated silencing of the GLP-1 receptor, and pretreatment with the protein
kinase A inhibitor H89. In conclusion, activation of GLP-1 receptors prevents oxidative stress-mediated apoptosis in human CPCs by interfering with JNK activation and may represent an important
mechanism for the cardioprotective effects of GLP-1. (Endocrinology 153: 5770 –5781, 2012)
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