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The efficacy and mechanism of apoptosis induction by hypericin-mediated sonodynamic therapy in THP-1 macrophages

Authors Li XS, Gao L, Zheng LB, Kou JY, Zhu X, Jiang YQ, Zhong ZY, Dan JH, Xu HB, Yang Y, Li H, Shi S, Cao WW, Zhao YJ, Tian Y, Yang LM

Received 4 October 2014

Accepted for publication 26 November 2014

Published 22 January 2015 Volume 2015:10(1) Pages 821—838

DOI https://doi.org/10.2147/IJN.S75398

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

Editor who approved publication: Dr Thomas J Webster

Xuesong Li,1,* Lei Gao,2,* Longbin Zheng,1 Jiayuan Kou,1 Xing Zhu,1 Yueqing Jiang,1 Zhaoyu Zhong,1 Juhua Dan,1 Haobo Xu,3 Yang Yang,3 Hong Li,1 Sa Shi,1 Wenwu Cao,4,5 Yajun Zhao,1 Ye Tian,1,3 Liming Yang1

1Department of Pathophysiology, Harbin Medical University, Harbin, People’s Republic of China; 2Electron Microscopy Centre, Harbin Medical University, Harbin, People’s Republic of China; 3Division of Cardiology, The First Affiliated Hospital, Harbin Medical University, Harbin, People’s Republic of China; 4Laboratory of Sono- and Photo-theranostic Technologies, Harbin Institute of Technology, Harbin, People’s Republic of China; 5Materials Research Institute, The Pennsylvania State University, University Park, PA, USA

*These authors contributed equally to this work

Purpose: To investigate the sonoactivity of hypericin (HY), together with its sonodynamic effect on THP-1 macrophages and the underlying mechanism.
Materials and methods: CCK-8 was used to examine cell viability. Confocal laser scanning microscopy was performed to assess the localization of HY in cells, reactive oxygen species (ROS) generation, and opening of the mitochondrial permeability transition pore (mPTP) after different treatments. Apoptosis was analyzed using Hoechst–propidium iodide and transmission electron microscopy. Mitochondrial membrane potential (ΔΨm) collapse was detected via fluorescence microscopy. Lipoprotein oxidation was determined in malondialdehyde (MDA) assays. Western blotting was conducted to determine the translocation of BAX and cytochrome C and the expression of apoptosis-related proteins.
Results: HY was sublocalized among the nuclei and the mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosome in the cytosol of THP-1 macrophages. Under low-intensity ultrasound irradiation, HY significantly decreased cell viability and induced apoptosis. Furthermore, greater ROS generation, higher MDA levels, and greater ΔΨm loss were observed in the sonodynamic therapy (SDT) group. Both ROS generation and MDA levels were significantly reduced by the ROS scavenger N-acetyl cysteine (NAC) and the singlet oxygen scavenger sodium azide. Most of the loss of ΔΨm was inhibited by pretreatment with NAC, sodium azide, and the mPTP inhibitor cyclosporin A (CsA). mPTP opening was induced upon SDT but was reduced by pretreatment with bongkrekic acid, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium, CsA, and NAC. Western blot analyses revealed translocation of BAX and cytochrome C, downregulated expression of Bcl-2, and upregulated expression of cleaved caspase-9, cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase in the SDT group, which were reversed by NAC.
Conclusion: HY mediated SDT-induced apoptosis in THP-1 macrophages via ROS generation. Then, the proapoptotic factor BAX translocated from the cytosol to the mitochondria, increasing the ratio of BAX/Bcl-2, and the mPTP opened to release cytochrome C. This study demonstrated the great potential of HY-mediated SDT for treating atherosclerosis.

Keywords: apoptosis, hypericin, sonodynamic therapy, mitochondria–caspase pathway, atherosclerosis

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