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International Journal of Molecular Medicine
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Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice

  • Authors:
    • Lei Wang
    • Zi Wang
    • Jiandang Shi
    • Qian Jiang
    • Hong Wang
    • Xu Li
    • Di Hao
  • View Affiliations / Copyright

    Affiliations: Cardiovascular and Cerebrovascular Drugs Research and Development Center, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin 300020, P.R. China, Department of Biochemistry and Molecular Biology, College of Life Sciences, Nankai University, Tianjin 300071, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 2098-2106
    |
    Published online on: July 31, 2018
       https://doi.org/10.3892/ijmm.2018.3797
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Abstract

The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) protects a variety of cell types against neuronal apoptosis by binding to apolipoprotein E receptor 2 (ApoER2). The present study aimed to determine the association between PCSK9/ApoER2 signaling and neuronal apoptosis following middle cerebral artery occlusion (MCAO) injury in hyperlipidemic mice. For this purpose, C57BL/6 mice fed with a high‑fat diet (HFD) for 6 weeks were exposed to MCAO. Subsequently, PCSK9 was inhibited by a lentiviral vector harboring short‑hairpin RNA (shRNA) targeting PCSK9, which was stereotaxically injected into the cerebral cortex of mice. At 48 h post‑ischemia, hematoxylin‑eosin staining and a terminal deoxynucleotidyl transferase dUTP nick end labeling assay were performed to determine cerebral tissue injury and apoptosis. PCSK9 and ApoER2 expression levels were assessed by reverse transcription‑quantitative polymerase chain reaction, immunohistochemistry and western blotting. The results indicated that hyperlipidemia and increased PCSK9 expression were evident in HFD mice. Cerebral histological injury and neuronal apoptosis, as well as PCSK9 and ApoER2 levels, which were increased upon ischemia in hyperlipidemic mice, were attenuated by PCSK9 shRNA treatment. These protective effects of PCSK9 shRNA interference were associated with decreased neuronal apoptosis and a reduced level of ApoER2 expression in the hippocampus and cortex. The data of the present study demonstrated that the PCSK9 shRNA‑mediated anti‑apoptotic effect induced by MCAO in hyperlipidemic mice is associated with ApoER2 downregulation, which may be a potential new therapy for stroke treatment in patients with hyperlipidemia.
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1 

Miao Y and Liao JK: Potential serum biomarkers in the pathophysiological processes of stroke. Expert Rev Neurother. 14:173–185. 2014. View Article : Google Scholar : PubMed/NCBI

2 

Kim E, Tolhurst AT, Qin LY, Chen XY, Febbraio M and Cho S: CD36/fatty acid translocase, an inflammatory mediator, is involved in hyperlipidemia-induced exacerbation in ischemic brain injury. J Neurosci. 28:4661–4670. 2008. View Article : Google Scholar : PubMed/NCBI

3 

Nozue T: Lipid lowering therapy and circulating PCSK9 concentration. J Atheroscler Thromb. 24:895–907. 2017. View Article : Google Scholar : PubMed/NCBI

4 

Sun H, Krauss RM, Chang JT and Teng BB: PCSK9 deficiency reduces atherosclerosis, apolipoprotein B secretion and endothelial dysfunction. J Lipid Res. 59:207–223. 2018. View Article : Google Scholar

5 

Yeramaneni S, Kleindorfer DO, Sucharew H, Alwell K, Moomaw CJ, Flaherty ML, Woo D, Adeoye O, Ferioli S, de Los Rios La, Rosa F, et al: Hyperlipidemia is associated with lower risk of poststroke mortality independent of statin use: A population-based study. Int J Stroke. 12:152–160. 2017. View Article : Google Scholar :

6 

Zhao W, An Z, Hong Y, Zhou G, Guo J, Zhang Y, Yang Y, Ning X and Wang J: Low total cholesterol level is the independent predictor of poor outcomes in patients with acute ischemic stroke: A hospital-based prospective study. BMC Neurol. 16:362016. View Article : Google Scholar : PubMed/NCBI

7 

Markaki I, Nilsson U, Kostulas K and Sjöstrand C: High cholesterol levels are associated with improved long-term survival after acute ischemic stroke. J Stroke Cerebrovasc Dis. 23:e47–e532014. View Article : Google Scholar

8 

Shapiro MD and Fazio S: PCSK9 and atherosclerosis-lipids and beyond. J Atheroscler Thromb. 24:462–472. 2017. View Article : Google Scholar : PubMed/NCBI

9 

Schulz R and Schlüter KD: PCSK9 targets important for lipid metabolism. Clin Res Cardiol Suppl. 12(Suppl 1): S2–S11. 2017. View Article : Google Scholar

10 

Kysenius K, Muggalla P, Mätlik K, Arumäe U and Huttunen HJ: PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling. Cell Mol Life Sci. 69:1903–1916. 2012. View Article : Google Scholar : PubMed/NCBI

11 

Liu M, Wu G, Baysarowich J, Kavana M, Addona GH, Bierilo KK, Mudgett JS, Pavlovic G, Sitlani A, Renger JJ, et al: PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain. J Lipid Res. 51:2611–2618. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Schulz R, Schlüter KD and Laufs U: Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9). Basic Res Cardiol. 110:42015. View Article : Google Scholar : PubMed/NCBI

13 

Li J, Liang X, Wang Y, Xu Z and Li G: Investigation of highly expressed PCSK9 in atherosclerotic plaques and ox-LDL-induced endothelial cell apoptosis. Mol Med Rep. 16:1817–1825. 2017. View Article : Google Scholar : PubMed/NCBI

14 

Wu CY, Tang ZH, Jiang L, Li XF, Jiang ZS and Liu LS: PCSK9 siRNA inhibits HUVEC apoptosis induced by ox-LDL via Bcl/Bax-caspase9-caspase3 pathway. Mol Cell Biochem. 359:347–358. 2012. View Article : Google Scholar

15 

Tang LL, Ye JY, Jiang SN and Zheng JS: 3,4-oxo-isopropylidene-shikimic acid inhibits cerebral ischemia-induced oxidative stress and neuronal apoptosis in rats. Am J Transl Res. 9:1764–1773. 2017.PubMed/NCBI

16 

Chiang LW, Grenier JM, Ettwiller L, Jenkins LP, Ficenec D, Martin J, Jin F, DiStefano PS and Wood A: An orchestrated gene expression component of neuronal programmed cell death revealed by cDNA array analysis. Proc Natl Acad Sci USA. 98:2814–2819. 2001. View Article : Google Scholar : PubMed/NCBI

17 

Bingham B, Shen R, Kotnis S, Lo CF, Ozenberger BA, Ghosh N, Kennedy JD, Jacobsen JS, Grenier JM, DiStefano PS, et al: Proapoptotic effects of NARC 1 (=PCSK9), the gene encoding a novel serine proteinase. Cytometry A. 69:1123–1131. 2006. View Article : Google Scholar : PubMed/NCBI

18 

Rousselet E, Marcinkiewicz J, Kriz J, Zhou A, Hatten ME, Prat A and Seidah NG: PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke. J Lipid Res. 52:1383–1391. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Beffert U, Nematollah Farsian F, Masiulis I, Hammer RE, Yoon SO, Giehl KM and Herz J: ApoE receptor 2 controls neuronal survival in the adult brain. Curr Biol. 16:2446–2452. 2006. View Article : Google Scholar : PubMed/NCBI

20 

Waltmann MD, Basford JE, Konaniah ES, Weintraub NL and Hui DY: Apolipoprotein E receptor-2 deficiency enhances macrophage susceptibility to lipid accumulation and cell death to augment atherosclerotic plaque progression and necrosis. Biochim Biophys Acta. 1842:1395–1405. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Morris GP, Wright AL, Tan RP, Gladbach A, Ittner LM and Vissel B: A comparative study of variables influencing ischemic injury in the longa and koizumi methods of intraluminal filament middle cerebral artery occlusion in mice. PLoS One. 11:e01485032016. View Article : Google Scholar : PubMed/NCBI

22 

Wang L, Wang Z, Yuan L, Hao D, Lü N and Li X: Shenfuqiangxin Capsule inhibits apoptosis through mitogen-activated protein kinase signal pathway in rats with cardio-renal syndrome induced by infrarenal aortic-clamping. J Tradit Chin Med. 37:80–87. 2017. View Article : Google Scholar : PubMed/NCBI

23 

Shi W, Wei X, Wang Z, Han H, Fu Y, Liu J, Zhang Y, Guo J, Dong C, Zhou D, et al: HDAC9 exacerbates endothelial injury in cerebral ischaemia/reperfusion injury. J Cell Mol Med. 20:1139–1149. 2016. View Article : Google Scholar : PubMed/NCBI

24 

Liu L, Wang Y and Yu Q: The PI3K/Akt signaling pathway exerts effects on the implantation of mouse embryos by regulating the expression of RhoA. Int J Mol Med. 33:1089–1096. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar

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Copy and paste a formatted citation
Spandidos Publications style
Wang L, Wang Z, Shi J, Jiang Q, Wang H, Li X and Hao D: Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice. Int J Mol Med 42: 2098-2106, 2018.
APA
Wang, L., Wang, Z., Shi, J., Jiang, Q., Wang, H., Li, X., & Hao, D. (2018). Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice. International Journal of Molecular Medicine, 42, 2098-2106. https://doi.org/10.3892/ijmm.2018.3797
MLA
Wang, L., Wang, Z., Shi, J., Jiang, Q., Wang, H., Li, X., Hao, D."Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice". International Journal of Molecular Medicine 42.4 (2018): 2098-2106.
Chicago
Wang, L., Wang, Z., Shi, J., Jiang, Q., Wang, H., Li, X., Hao, D."Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice". International Journal of Molecular Medicine 42, no. 4 (2018): 2098-2106. https://doi.org/10.3892/ijmm.2018.3797
Copy and paste a formatted citation
x
Spandidos Publications style
Wang L, Wang Z, Shi J, Jiang Q, Wang H, Li X and Hao D: Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice. Int J Mol Med 42: 2098-2106, 2018.
APA
Wang, L., Wang, Z., Shi, J., Jiang, Q., Wang, H., Li, X., & Hao, D. (2018). Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice. International Journal of Molecular Medicine, 42, 2098-2106. https://doi.org/10.3892/ijmm.2018.3797
MLA
Wang, L., Wang, Z., Shi, J., Jiang, Q., Wang, H., Li, X., Hao, D."Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice". International Journal of Molecular Medicine 42.4 (2018): 2098-2106.
Chicago
Wang, L., Wang, Z., Shi, J., Jiang, Q., Wang, H., Li, X., Hao, D."Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice". International Journal of Molecular Medicine 42, no. 4 (2018): 2098-2106. https://doi.org/10.3892/ijmm.2018.3797
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