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Atorvastatin inhibits the apoptosis of human umbilical vein endothelial cells induced by angiotensin II via the lysosomal-mitochondrial axis

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Abstract

This study was aimed to evaluate lysosomes–mitochondria cross-signaling in angiotensin II (Ang II)-induced apoptosis of human umbilical vein endothelial cells (HUVECs) and whether atorvastatin played a protective role via lysosomal-mitochondrial axis. Apoptosis was detected by flow cytometry, Hoechst 33342 and AO/EB assay. The temporal relationship of lysosomal and mitochondrial permeabilization was established. Activity of Cathepsin D (CTSD) was suppressed by pharmacological and genetic approaches. Proteins production were measured by western blotting. Our study showed that Ang II could induce the apoptosis of HUVECs in a dose-depended and time-depended manner. Exposure to 1 μM Ang II for 24 h resulted in mitochondrial depolarization, cytochrome c release, and increased ROS production. Lysosomal permeabilization and CTSD redistribution into the cytoplasm occurred several hours prior to mitochondrial dysfunction. These effects were all suppressed by atorvastatin. Either pharmacological or genetic inhibition of CTSD preserved mitochondrial function and decreased apoptosis in HUVECs. Most importantly, we found that the protective effect of atorvastatin was significantly greater than pharmacological or genetic inhibition of CTSD. Finally, overexpression of CTSD without exposure to Ang II had no effect on mitochondrial function and apoptosis. Our data strongly suggested that Ang II induced apoptosis through the lysosomal-mitochondrial axis in HUVECs. Furthermore, atorvastatin played an important role in the regulation of lysosomes and mitochondria stability, resulting in an antagonistic role against Ang II on HUVECs.

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Acknowledgments

This work was supported by National Natural Science Foundation of China [Grant No. 81470417] and Natural Science Foundation of Liaoning Province [Grant No. 2013021090].

Author Contributions

Ye Chang, Zhao Li and Yingxian Sun conceived and designed the experiments; Ye Chang, Yuan Li, Ning Ye, Xiaofan Guo and Guozhe Sun performed the experiments; Ye Chang analyzed the data; Ye Chang wrote the paper.

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Authors and Affiliations

  1. Department of Cardiology, The First Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning, People’s Republic of China

    Ye Chang, Yuan Li, Ning Ye, Xiaofan Guo, Zhao Li, Guozhe Sun & Yingxian Sun

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  1. Ye Chang
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Correspondence to Yingxian Sun.

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Chang, Y., Li, Y., Ye, N. et al. Atorvastatin inhibits the apoptosis of human umbilical vein endothelial cells induced by angiotensin II via the lysosomal-mitochondrial axis. Apoptosis 21, 977–996 (2016). https://doi.org/10.1007/s10495-016-1271-0

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