Glucagon-like peptide-1 attenuates endoplasmic reticulum stress–induced apoptosis in H9c2 cardiomyocytes during hypoxia/reoxygenation through the GLP-1R/PI3K/Akt pathways
Endoplasmic reticulum (ER) stress–induced apoptosis is a major cause of myocardial ischemia/reperfusion (I/R) injury. Emerging evidence indicates that glucagon-like peptide-1 (GLP-1) has potential cardioprotective effects. However, the precise mechanisms underlying the involvement of GLP-1 in I/R injury remain largely unknown. In the present study, we aimed to determine whether GLP-1 attenuates hypoxia/reoxygenation (H/R) injury in cardiomyocytes and to further elucidate the underlying signaling pathway. The results indicate that GLP-1 reversed the increased apoptotic ratio, the increased lactate dehydrogenase (LDH) levels, the reduced cell viability, the increased Caspase-3 activity, and the increased Bax/Bcl-2 ratio caused by H/R. Importantly, GLP-1 significantly decreased the expression of H/R-induced ER stress proteins (GRP78, CHOP) and Caspase-12. In addition, we found that GLP-1 increased the expression of p-Akt in H9c2 cells with H/R injuries, and that the protective action of GLP-1 against H/R-induced injury was blocked by the GLP-1 receptor (GLP-1R) inhibitor Exendin9-39 and the PI3K inhibitor LY294002. Exendin9-39 and LY294002 also blocked the downregulation of ER stress protein expression by GLP-1, after H/R injury. Therefore, we have shown that GLP-1 exerts its cardioprotective effects by alleviating ER stress–induced apoptosis due to H/R injury and that these effects are most likely associated with the activation of GLP-1R/PI3K/Akt signaling pathway.
KeywordsHypoxia/reoxygenation injury Endoplasmic reticulum stress Glucagon-like peptide-1 H9c2 PI3K/Akt pathway
We thank professor Lei Yang (Basic Medical Science College, Jiujiang University, Jiujiang, Jiangxi Province, China) for providing intellectual content of critical importance to the work described.
X.G. designed the study. G.G., J.Z., and S.L. performed the experiments and collected the data. W.H. and Y.G. analyzed and interpreted the experimental data. X.G. and G.G. prepared the manuscript.
This research study was funded by the National Natural Science Foundation of China (Grant No. 81660152) and the Natural Science Foundation of Jiangxi Province (Grant No.20181BAB205004).
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Conflicts of interest
The authors declare that they have no conflict of interest.
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