Abstract
Apelin is the endogenous ligand for the G protein-coupled receptor APJ, and plays important roles in the cardiovascular system. Our previous studies showed that apelin-13 promotes the hypertrophy of H9c2 rat cardiomyocytes through the PI3K-autophagy pathway. The aim of this study was to explore what roles ER stress and autophagy played in apelin-13-induced hypertrophy of cardiomyocytes in vitro. Treatment of H9c2 cells with apelin-13 (0.001–2 μmol/L) dose-dependently increased the production of ROS and the expression levels of NADPH oxidase 4 (NOX4). Knockdown of Nox4 with siRNAs effectively prevented the reduction of GSH/GSSG ratio in apelin-13-treated cells. Furthermore, apelin-13 treatment dose-dependently increased the expression of Bip and CHOP, two ER stress markers, in the cells. Knockdown of APJ or Nox4 with the corresponding siRNAs, or application of NADPH inhibitor DPI blocked apelin-13-induced increases in Bip and CHOP expression. Moreover, apelin-13 treatment increased the formation of autophagosome and ER fragments and the LC3 puncta in the ER of the cells. Knockdown of APJ, Nox4, Bip or CHOP with the corresponding siRNAs, or application of DPI or salubrinal attenuated apelin-13-induced overexpression of LC3-II/I and beclin 1. Finally, knockdown of Nox4, Bip or CHOP with the corresponding siRNAs, or application of salubrinal significantly suppressed apelin-13-induced increases in the cell diameter, volume and protein contents. Our results demonstrate that ER stress-autophagy is involved in apelin-13-induced H9c2 cell hypertrophy.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (81503074, 81270420, 81470434, and 81670265), Hunan Provincial Natural Science Foundation (14JJ3102; 2017JJ2227), China Postdoctoral Science Foundation (2014M560647). We especially thank Bing-bing WANG (Assistant Professor, Perinatal Biology Laboratory, Division of Maternal-Fetal Medicine, Rutgers University-Robert Wood Johnson Medical School, USA) for the English language correction.
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Xie, F., Wu, D., Huang, Sf. et al. The endoplasmic reticulum stress-autophagy pathway is involved in apelin-13-induced cardiomyocyte hypertrophy in vitro. Acta Pharmacol Sin 38, 1589–1600 (2017). https://doi.org/10.1038/aps.2017.97
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DOI: https://doi.org/10.1038/aps.2017.97
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