Open Access

Simvastatin promotes endothelial dysfunction by activating the Wnt/β‑catenin pathway under oxidative stress

  • Authors:
    • Zhiqiang He
    • Xinyue Du
    • Yifan Wu
    • Lingyue Hua
    • Linxi Wan
    • Nianlong Yan
  • View Affiliations

  • Published online on: August 9, 2019     https://doi.org/10.3892/ijmm.2019.4310
  • Pages: 1289-1298
  • Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Atherosclerosis is a major pathogenic factor in patients with cardiovascular diseases, and endothelial dysfunction (ED) plays a primary role in its occurrence and development. Simvastatin is a lipid‑lowering drug, which is commonly used to prevent or treat risk factors of cardiovascular diseases with a significant anti‑atherogenic effect. However, its impact on endothelial cells under conditions of oxidative stress and broader mechanisms of action remain unclear. The present study evaluated the effect of simvastatin on human umbilical vein endothelial cells (HUVECs) under oxidative stress with H2O2, and the associated mechanisms. At a high dose (1 µM), simvastatin exacerbated H2O2‑induced endothelial cell dysfunction. Moreover, inhibition of the Wnt/β‑catenin pathway by salinomycin significantly suppressed the simvastatin‑associated HUVEC dysfunction. Western blot analysis further demonstrated that simvastatin promoted the phosphorylation of low‑density lipoprotein receptor‑related protein 6 (LRP6) and activated the Wnt/β‑catenin pathway. Simvastatin also activated endoplasmic reticulum (ER) stress, which was reversed by salinomycin treatment. Based on these results, it was hypothesized that simvastatin may promote ER stress by facilitating LRP6 phosphorylation and the subsequent activation of the Wnt/β‑catenin pathway, thereby enhancing H2O2‑induced ED. Therefore, high‑dose simvastatin treatment could have potential toxic side effects, indicating the need for close clinical management, monitoring and patient selection.

References

1 

Frostegård J: Immunity, atherosclerosis and cardiovascular disease. BMC Med. 11:1172013. View Article : Google Scholar : PubMed/NCBI

2 

Shah P, Bajaj S, Virk H, Bikkina M and Shamoon F: Rapid progression of coronary atherosclerosis: A review. Thrombosis. 2015:6349832015. View Article : Google Scholar

3 

Kerr GE, Young JC, Horvay K, Abud HE and Loveland KL: Regulated Wnt/beta-catenin signaling sustains adult spermatogenesis in mice. Biol Reprod. 90:32014. View Article : Google Scholar

4 

Clevers H and Nusse R: Wnt/β-catenin signaling and disease. Cell. 149:1192–1205. 2012. View Article : Google Scholar : PubMed/NCBI

5 

Polakis P: Drugging Wnt signalling in cancer. EMBO J. 31:2737–2746. 2012. View Article : Google Scholar : PubMed/NCBI

6 

Gelfand BD, Meller J, Pryor AW, Kahn M, Bortz PD, Wamhoff BR and Blackman BR: Hemodynamic activation of beta-catenin and T-cell-specific transcription factor signaling in vascular endothelium regulates fibronectin expression. Arterioscler Thromb Vasc Biol. 31:1625–1633. 2011. View Article : Google Scholar : PubMed/NCBI

7 

Ueland T, Otterdal K, Lekva T, Halvorsen B, Gabrielsen A, Sandberg WJ, Paulsson-Berne G, Pedersen TM, Folkersen L, Gullestad L, et al: Dickkopf-1 enhances inflammatory interaction between platelets and endothelial cells and shows increased expression in atherosclerosis. Arterioscler Thromb Vasc Biol. 29:1228–1234. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Tsaousi A, Mill C and George SJ: The Wnt pathways in vascular disease: Lessons from vascular development. Curr Opin Lipidol. 22:350–357. 2011. View Article : Google Scholar : PubMed/NCBI

9 

Zerlin M, Julius MA and Kitajewski J: Wnt/Frizzled signaling in angiogenesis. Angiogenesis. 11:63–69. 2008. View Article : Google Scholar : PubMed/NCBI

10 

Zhang P, Hua L, Hou H, Du X, He Z, Liu M, Hu X and Yan N: Sphingomyelin synthase 2 promotes H2O2-induced endothelial dysfunction by activating the Wnt/β-catenin signaling pathway. Int J Mol Med. 42:3344–3354. 2018.PubMed/NCBI

11 

Shinozaki S, Chiba T, Kokame K, Miyata T, Kaneko E and Shimokado K: A deficiency of Herp, an endoplasmic reticulum stress protein, suppresses atherosclerosis in ApoE knockout mice by attenuating inflammatory responses. PLoS One. 8:e752492013. View Article : Google Scholar : PubMed/NCBI

12 

Sozen E, Karademir B and Ozer NK: Basic mechanisms in endoplasmic reticulum stress and relation to cardiovascular diseases. Free Radic Biol Med. 78:30–41. 2015. View Article : Google Scholar

13 

Huang A, Patel S, McAlpine CS and Werstuck GH: The role of endoplasmic reticulum stress-glycogen synthase kinase-3 signaling in atherogenesis. Int J Mol Sci. 19:E16072018. View Article : Google Scholar : PubMed/NCBI

14 

Halleskog C, Mulder J, Dahlström J, Mackie K, Schulte G, Hortobágyi T, Tanila H, Kumar Puli L, Färber K and Harkany T: WNT signaling in activated microglia is proinflammatory. Glia. 59:119–131. 2011. View Article : Google Scholar

15 

Amodio G, Moltedo O, Faraonio R and Remondelli P: Targeting the endoplasmic reticulum unfolded protein response to counteract the oxidative stress-induced endothelial dysfunction. Oxid Med Cell Longev. 2018:49462892018. View Article : Google Scholar : PubMed/NCBI

16 

Hong J, Kim K, Park E, Lee J, Markofski MM, Marrelli SP and Park Y: Exercise ameliorates endoplasmic reticulum stress-mediated vascular dysfunction in mesenteric arteries in atherosclerosis. Sci Rep. 8:79382018. View Article : Google Scholar : PubMed/NCBI

17 

Garshick M and Underberg JA: The use of primary prevention statin therapy in those predisposed to atherosclerosis. Curr Atheroscler Rep. 19:482017. View Article : Google Scholar : PubMed/NCBI

18 

Gao K, Shen Z, Yuan Y, Han D, Song C, Guo Y and Mei X: Simvastatin inhibits neural cell apoptosis and promotes loco-motor recovery via activation of Wnt/β-catenin signaling pathway after spinal cord injury. J Neurochem. 138:139–149. 2016. View Article : Google Scholar :

19 

Robin NC, Agoston Z, Biechele TL, James RG, Berndt JD and Moon RT: Simvastatin promotes adult hippocampal neurogenesis by enhancing Wnt/β-catenin signaling. Stem Cell Reports. 2:9–17. 2013. View Article : Google Scholar

20 

Duan J, Yu Y, Li Y, Yu Y, Li Y, Zhou X, Huang P and Sun Z: Toxic effect of silica nanoparticles on endothelial cells through DNA damage response via Chk1-dependent G2/M checkpoint. PLoS One. 8:e620872013. View Article : Google Scholar : PubMed/NCBI

21 

Valenta T, Hausmann G and Basler K: The many faces and functions of β-catenin. EMBO J. 31:2714–2736. 2012. View Article : Google Scholar : PubMed/NCBI

22 

Li Y, Qin X, Li P, Zhang H, Lin T, Miao Z and Ma S: Isobavachalcone isolated from Psoralea corylifolia inhibits cell proliferation and induces apoptosis via inhibiting the AKT/GSK-3β/β-catenin pathway in colorectal cancer cells. Drug Des Devel Ther. 13:1449–1460. 2019. View Article : Google Scholar :

23 

Wang LR, Kim SH and Baek SS: Effects of treadmill exercise on the anxiety-like behavior through modulation of GSK3β/β-catenin signaling in the maternal separation rat pup. J Exerc Rehabil. 15:206–212. 2019. View Article : Google Scholar : PubMed/NCBI

24 

Duvetorp A, Olsen RS, Nyström H, Skarstedt M, Dienus O, Mrowietz U, Söderman J and Seifert O: Expression of low-density lipoprotein-related receptors 5 and 6 (LRP5/6) in psoriasis skin. Exp Dermatol. 26:1033–1038. 2017. View Article : Google Scholar : PubMed/NCBI

25 

Harisa GI, Alomrani AH and Badran MM: Simvastatin-loaded nanostructured lipid carriers attenuate the atherogenic risk of erythrocytes in hyperlipidemic rats. Eur J Pharm Sci. 96:62–71. 2017. View Article : Google Scholar

26 

Yu X, Yan N, Li Z, Hua Y and Chen W: FGF19 sustains the high proliferative ability of keratinocytes in psoriasis through the regulation of Wnt/GSK-3β/β-catenin signaling via FGFR4. Clin Exp Pharmacol Physiol. 46:761–769. 2019. View Article : Google Scholar : PubMed/NCBI

27 

Chung CL, Wang SW, Sun WC, Shu CW, Kao YC, Shiao MS and Chen CL: Sorafenib suppresses TGF-β responses by inducing caveolae/lipid raft-mediated internalization/degradation of cell-surface type II TGF-β receptors: Implications in development of effective adjunctive therapy for hepatocellular carcinoma. Biochem Pharmacol. 154:39–53. 2018. View Article : Google Scholar : PubMed/NCBI

28 

Özhan G, Sezgin E, Wehner D, Pfister AS, Kühl SJ, Kagermeier- Schenk B, Kühl M, Schwille P and Weidinger G: Lypd6 enhances Wnt/β-catenin signaling by promoting Lrp6 phosphorylation in raft plasma membrane domains. Dev Cell. 26:331–345. 2013. View Article : Google Scholar

29 

Li Z, Yang Y, Gao Y, Wu X, Yang X, Zhu Y, Yang H, Wu L, Yang C and Song L: Elevated expression of flotillin-1 is associated with lymph node metastasis and poor prognosis in early-stage cervical cancer. Am J Cancer Res. 6:38–50. 2015.

30 

Haack F, Lemcke H, Ewald R, Rharass T and Uhrmacher AM: Spatio-temporal model of endogenous ROS and raft-dependent WNT/beta-catenin signaling driving cell fate commitment in human neural progenitor cells. PLoS Comput Biol. 11:e10041062015. View Article : Google Scholar : PubMed/NCBI

31 

Badana AK, Chintala M, Gavara MM, Naik S, Kumari S, Kappala VR, Iska BR and Malla RR: Lipid rafts disruption induces apoptosis by attenuating expression of LRP6 and survivin in triple negative breast cancer. Biomed Pharmacother. 97:359–368. 2018. View Article : Google Scholar

32 

Cao L, Lei H, Chang MZ, Liu ZQ and Bie XH: Down-regulation of 14-3-3β exerts anti-cancer effects through inducing ER stress in human glioma U87 cells: Involvement of CHOP-Wnt pathway. Biochem Biophys Res Commun. 462:389–395. 2015. View Article : Google Scholar : PubMed/NCBI

33 

Jia X, Chen Y, Zhao X, Lv C and Yan J: Oncolytic vaccinia virus inhibits human hepatocellular carcinoma MHCC97-H cell proliferation via endoplasmic reticulum stress, autophagy and Wnt pathways. J Gene Med. 18:211–219. 2016. View Article : Google Scholar : PubMed/NCBI

34 

He Z, He X, Liu M, Hua L, Wang T, Liu Q, Chen L and Yan N: Simvastatin attenuates H2O2-induced endothelial cell dysfunction by reducing endoplasmic reticulum stress. Molecules. 24:E17822019. View Article : Google Scholar

35 

Sun H, Wang X, Liu K, Guo M, Zhang Y, Ying QL and Ye S: β-catenin coordinates with Jup and the TCF1/GATA6 axis to regulate human embryonic stem cell fate. Dev Biol. 431:272–281. 2017. View Article : Google Scholar : PubMed/NCBI

36 

Kim J, Kim J, Kim DW, Ha Y, Ihm MH, Kim H, Song K and Lee I: Wnt5a induces endothelial inflammation via beta-catenin-independent signaling. J Immunol. 185:1274–1282. 2010. View Article : Google Scholar : PubMed/NCBI

37 

Vikram A, Kim YR, Kumar S, Naqvi A, Hoffman TA, Kumar A, Miller FJ Jr, Kim CS and Irani K: Canonical Wnt signaling induces vascular endothelial dysfunction via p66 Shc -regulated reactive oxygen species. Arterioscler Thromb Vasc Biol. 34:2301–2309. 2014. View Article : Google Scholar : PubMed/NCBI

38 

Martinez-Font E, Felipe-Abrio I, Calabuig-Fariñas S, Ramos R, Terrasa J, Vögler O, Alemany R, Martín-Broto J and Obrador- Hevia A: Disruption of TCF/β-catenin binding impairs Wnt signaling and induces apoptosis in soft tissue sarcoma cells. Mol Cancer Ther. 16:1166–1176. 2017. View Article : Google Scholar : PubMed/NCBI

39 

Zhang Z, Wu S, Muhammad S, Ren Q and Sun C: miR-103/107 promote ER stress mediated apoptosis via targeting the Wnt3a/β-catenin/ATF6 pathway in preadipocytes. J Lipid Res. 59:843–853. 2018. View Article : Google Scholar : PubMed/NCBI

40 

Karlson BW, Palmer MK, Nicholls SJ, Lundman P and Barter PJ: Doses of rosuvastatin, atorvastatin and simvastatin that induce equal reductions in LDL-C and non-HDL-C: Results from the VOYAGER meta-analysis. Eur J Prev Cardiol. 23:744–747. 2016. View Article : Google Scholar

41 

Barale C, Frascaroli C, Cavalot F and Russo I: Hypercholesterolemia impairs the Glucagon-like peptide 1 action on platelets: Effects of a lipid-lowering treatment with simvastatin. Thromb Res. 180:74–85. 2019. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October 2019
Volume 44 Issue 4

Print ISSN: 1107-3756
Online ISSN:1791-244X

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
He, Z., Du, X., Wu, Y., Hua, L., Wan, L., & Yan, N. (2019). Simvastatin promotes endothelial dysfunction by activating the Wnt/β‑catenin pathway under oxidative stress. International Journal of Molecular Medicine, 44, 1289-1298. https://doi.org/10.3892/ijmm.2019.4310
MLA
He, Z., Du, X., Wu, Y., Hua, L., Wan, L., Yan, N."Simvastatin promotes endothelial dysfunction by activating the Wnt/β‑catenin pathway under oxidative stress". International Journal of Molecular Medicine 44.4 (2019): 1289-1298.
Chicago
He, Z., Du, X., Wu, Y., Hua, L., Wan, L., Yan, N."Simvastatin promotes endothelial dysfunction by activating the Wnt/β‑catenin pathway under oxidative stress". International Journal of Molecular Medicine 44, no. 4 (2019): 1289-1298. https://doi.org/10.3892/ijmm.2019.4310