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Ticagrelor suppresses oxidized low‑density lipoprotein‑induced endothelial cell apoptosis and alleviates atherosclerosis in ApoE‑/‑ mice via downregulation of PCSK9

  • Authors:
    • Xiaodong Xia
    • Jiao Li
    • Xue Liang
    • Shengjie Zhang
    • Tong Liu
    • Jinying Liu
    • Muhammad Arif
    • Guangping Li
  • View Affiliations / Copyright

    Affiliations: Department of Cardiology, Second Hospital of Tianjin Medical University, Tianjin Key Laboratory of Ionic‑Molecular Function of Cardiovascular Disease, Tianjin Institute of Cardiology, Tianjin 300211, P.R. China, Department of Pharmacy, The Second People's Hospital of Liaocheng, Shandong, Liaocheng 252600, P.R. China, College of Life Science, Nankai University, Tianjin 300071, P.R. China
    Copyright: © Xia et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 1453-1462
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    Published online on: December 20, 2018
       https://doi.org/10.3892/mmr.2018.9779
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Abstract

Although ticagrelor has been demonstrated to possess an anti‑atherosclerosis (AS) effect, its underlying mechanism remains unclear. In the present study, it was investigated whether ticagrelor reduces oxidized low‑density lipoprotein (ox‑LDL)‑induced endothelial cell apoptosis, an initial step for the development of AS, and alleviates AS in apolipoprotein‑E‑deficient (ApoE‑/‑) mice by inhibiting the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9). The human endothelial cell line EAhy926 was treated with ox‑LDL, ox‑LDL + ticagrelor (40 µmol/l) and ox‑LDL + ticagrelor (60 µmol/l) for 24 h. Cell apoptosis was detected using Annexin V‑fluorescein isothiocyanate/propidium iodide staining. The expression levels of PCSK9, apoptosis‑associated proteins and signaling pathways were determined by reverse transcription‑quantitative polymerase chain reaction and western blotting. ApoE‑/‑ mice fed a high‑fat diet were used to induce an AS model. After 20 weeks, ApoE‑/‑ mice were randomly assigned to receive saline or ticagrelor intragastrically for 10 days. The formation of atherosclerotic plaques was detected by hematoxylin and eosin staining. The expression of PCSK9 in the arterial tissues was measured by immunohistochemistry. The results demonstrated that treatment with ticagrelor was able to decrease ox‑LDL‑induced apoptosis in a concentration‑dependent manner (40 µmol/l vs. ox‑LDL, 17.58±2.66 vs. 27.25±5.54%; 60 µmol/l vs. ox‑LDL, 12.26±1.54 vs. 27.25±5.54%). The mRNA and protein expression level of PCSK9 significantly decreased following treatment with ticagrelor, accompanied with upregulation of B‑cell lymphoma (Bcl) 2 and downregulation of Bcl‑2 associated X, apoptosis regulator, caspase‑3, p38, phosphorylated‑(p) p38, p‑c‑Jun N‑terminal kinases (JNK), p‑extracellular signal‑regulated kinases and the ratio of p‑JNK to JNK. Histological analysis of arterial tissues revealed ticagrelor markedly decreased the atherosclerotic plaque area and inhibited the expression of PCSK9. The present results suggested that ticagrelor may alleviate AS via downregulation of PCSK9‑mediated endothelial cell apoptosis, which may be JNK‑dependent.
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Copy and paste a formatted citation
Spandidos Publications style
Xia X, Li J, Liang X, Zhang S, Liu T, Liu J, Arif M and Li G: Ticagrelor suppresses oxidized low‑density lipoprotein‑induced endothelial cell apoptosis and alleviates atherosclerosis in ApoE‑/‑ mice via downregulation of PCSK9. Mol Med Rep 19: 1453-1462, 2019.
APA
Xia, X., Li, J., Liang, X., Zhang, S., Liu, T., Liu, J. ... Li, G. (2019). Ticagrelor suppresses oxidized low‑density lipoprotein‑induced endothelial cell apoptosis and alleviates atherosclerosis in ApoE‑/‑ mice via downregulation of PCSK9. Molecular Medicine Reports, 19, 1453-1462. https://doi.org/10.3892/mmr.2018.9779
MLA
Xia, X., Li, J., Liang, X., Zhang, S., Liu, T., Liu, J., Arif, M., Li, G."Ticagrelor suppresses oxidized low‑density lipoprotein‑induced endothelial cell apoptosis and alleviates atherosclerosis in ApoE‑/‑ mice via downregulation of PCSK9". Molecular Medicine Reports 19.3 (2019): 1453-1462.
Chicago
Xia, X., Li, J., Liang, X., Zhang, S., Liu, T., Liu, J., Arif, M., Li, G."Ticagrelor suppresses oxidized low‑density lipoprotein‑induced endothelial cell apoptosis and alleviates atherosclerosis in ApoE‑/‑ mice via downregulation of PCSK9". Molecular Medicine Reports 19, no. 3 (2019): 1453-1462. https://doi.org/10.3892/mmr.2018.9779
Copy and paste a formatted citation
x
Spandidos Publications style
Xia X, Li J, Liang X, Zhang S, Liu T, Liu J, Arif M and Li G: Ticagrelor suppresses oxidized low‑density lipoprotein‑induced endothelial cell apoptosis and alleviates atherosclerosis in ApoE‑/‑ mice via downregulation of PCSK9. Mol Med Rep 19: 1453-1462, 2019.
APA
Xia, X., Li, J., Liang, X., Zhang, S., Liu, T., Liu, J. ... Li, G. (2019). Ticagrelor suppresses oxidized low‑density lipoprotein‑induced endothelial cell apoptosis and alleviates atherosclerosis in ApoE‑/‑ mice via downregulation of PCSK9. Molecular Medicine Reports, 19, 1453-1462. https://doi.org/10.3892/mmr.2018.9779
MLA
Xia, X., Li, J., Liang, X., Zhang, S., Liu, T., Liu, J., Arif, M., Li, G."Ticagrelor suppresses oxidized low‑density lipoprotein‑induced endothelial cell apoptosis and alleviates atherosclerosis in ApoE‑/‑ mice via downregulation of PCSK9". Molecular Medicine Reports 19.3 (2019): 1453-1462.
Chicago
Xia, X., Li, J., Liang, X., Zhang, S., Liu, T., Liu, J., Arif, M., Li, G."Ticagrelor suppresses oxidized low‑density lipoprotein‑induced endothelial cell apoptosis and alleviates atherosclerosis in ApoE‑/‑ mice via downregulation of PCSK9". Molecular Medicine Reports 19, no. 3 (2019): 1453-1462. https://doi.org/10.3892/mmr.2018.9779
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