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Article

ox-LDL downregulates eNOS activity via LOX-1-mediated endoplasmic reticulum stress

  • Authors:
    • Jie Zhou
    • Morad Dirhem Naji Abid
    • Yufang Xiong
    • Qing Chen
    • Juan Chen
  • View Affiliations / Copyright

    Affiliations: Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China, Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
  • Pages: 1442-1450
    |
    Published online on: September 30, 2013
       https://doi.org/10.3892/ijmm.2013.1513
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Abstract

Vascular endothelial injury induced by oxidized low-density lipoprotein (ox-LDL) has been implicated in the early stages of the pathogenesis of atherosclerosis. In this study, we incubated bovine aortic endothelial cells (BAECs) with ox-LDL (100 µg/ml) in order to induce endoplasmic reticulum (ER) stress and to investigate the regulation of endothelial nitric oxide synthase (eNOS). Within 4 h of exposure, ox-LDL rapidly induced ER stress, as demonstrated by the measurements of proline-rich extensin-like receptor kinase (PERK) and glucose-regulated protein (GRP)78. ox-LDL induced the rapid dephosphorylation of eNOS at Ser1179 and a subsequent decrease in eNOS activity. This effect appeared to be highly specific as no change was observed in the levels of phosphorylated eNOS at Thr497 or eNOS protein. Of note, a simultaneous decrease was also observed in the active (phosphorylated) form of Akt (Thr308/Ser473), which has been demonstrated to phosphorylate eNOS at Ser1179. Further analysis indicated that Brefeldin A (BFA), an ER stress-inducing reagent, induced the rapid dephosphorylation of Akt and eNOS at Ser1179. 4-Phenylbutyric acid (PBA), an inhibitor of ER stress, blocked the ox-LDL-induced dephosphorylation of Akt and eNOS. Furthermore, JTX20, a lectin-like ox-LDL receptor-1 (LOX-1) blocking antibody significantly eliminated the ability of ox-LDL to mediate the dephosphorylation of eNOS and Akt. Our results indicate that the downregulation of eNOS by ox-LDL, as driven by LOX-1-mediated ER stress, is associated with the PI3K-Akt-eNOS signaling pathway.
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1 

Ross R: The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 362:801–809. 1993. View Article : Google Scholar : PubMed/NCBI

2 

Stocker R and Keaney JF Jr: Role of oxidative modifications in atherosclerosis. Physiol Rev. 84:1381–1478. 2004. View Article : Google Scholar : PubMed/NCBI

3 

Griffith OW and Stuehr DJ: Nitric oxide synthases: properties and catalytic mechanism. Annu Rev Physiol. 57:707–736. 1995. View Article : Google Scholar : PubMed/NCBI

4 

Cheng J, Ou JS, Singh H, et al: 20-hydroxyeicosatetraenoic acid causes endothelial dysfunction via eNOS uncoupling. Am J Physiol Heart Circ Physiol. 294:H1018–H1026. 2008. View Article : Google Scholar : PubMed/NCBI

5 

Sawamura T, Kume N, Aoyama T, et al: An endothelial receptor for oxidized low-density lipoprotein. Nature. 386:73–77. 1997. View Article : Google Scholar : PubMed/NCBI

6 

Sugimoto K, Ishibashi T, Sawamura T, et al: LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-density lipoprotein in endothelial cells. Cardiovasc Res. 84:127–136. 2009. View Article : Google Scholar : PubMed/NCBI

7 

Ogura S, Kakino A, Sato Y, et al: Lox-1: the multifunctional receptor underlying cardiovascular dysfunction. Circ J. 73:1993–1999. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Fulton D, Gratton JP, McCabe TJ, et al: Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 399:597–601. 1999. View Article : Google Scholar : PubMed/NCBI

9 

Dimmeler S, Fleming I, Fisslthaler B, et al: Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 399:601–605. 1999. View Article : Google Scholar : PubMed/NCBI

10 

Sanson M, Auge N, Vindis C, et al: Oxidized low-density lipoproteins trigger endoplasmic reticulum stress in vascular cells: prevention by oxygen-regulated protein 150 expression. Circ Res. 104:328–336. 2009. View Article : Google Scholar

11 

Tu BP and Weissman JS: Oxidative protein folding in eukaryotes: mechanisms and consequences. J Cell Biol. 164:341–346. 2004. View Article : Google Scholar : PubMed/NCBI

12 

Banhegyi G, Csala M, Szarka A, et al: Role of ascorbate in oxidative protein folding. Biofactors. 17:37–46. 2003. View Article : Google Scholar : PubMed/NCBI

13 

Zhou J, Werstuck GH, Lhotak S, et al: Association of multiple cellular stress pathways with accelerated atherosclerosis in hyperhomocysteinemic apolipoprotein E-deficient mice. Circulation. 110:207–213. 2004. View Article : Google Scholar : PubMed/NCBI

14 

Myoishi M, Hao H, Minamino T, et al: Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome. Circulation. 116:1226–1233. 2007. View Article : Google Scholar : PubMed/NCBI

15 

Xu C, Bailly-Maitre B and Reed JC: Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest. 115:2656–2664. 2005. View Article : Google Scholar : PubMed/NCBI

16 

Dong Y, Zhang M, Liang B, et al: Reduction of AMP-activated protein kinase alpha2 increases endoplasmic reticulum stress and atherosclerosis in vivo. Circulation. 121:792–803. 2010. View Article : Google Scholar : PubMed/NCBI

17 

Hyoda K, Hosoi T, Horie N, et al: PI3K-Akt inactivation induced CHOP expression in endoplasmic reticulum-stressed cells. Biochem Biophys Res Commun. 340:286–290. 2006. View Article : Google Scholar : PubMed/NCBI

18 

Sessa WC, Harrison JK, Luthin DR, et al: Genomic analysis and expression patterns reveal distinct genes for endothelial and brain nitric oxide synthase. Hypertension. 21:934–938. 1993. View Article : Google Scholar : PubMed/NCBI

19 

Sessa WC, Barber CM and Lynch KR: Mutation of N-myristoylation site converts endothelial cell nitric oxide synthase from a membrane to a cytosolic protein. Circ Res. 72:921–924. 1993. View Article : Google Scholar : PubMed/NCBI

20 

Rosenkranz-Weiss P, Sessa WC, Milstien S, et al: Regulation of nitric oxide synthesis by proinflammatory cytokines in human umbilical vein endothelial cells. Elevations in tetrahydrobiopterin levels enhance endothelial nitric oxide synthase specific activity. J Clin Invest. 93:2236–2243. 1994. View Article : Google Scholar

21 

Wei Q and Xia Y: Proteasome inhibition down-regulates endothelial nitric-oxide synthase phosphorylation and function. J Biol Chem. 281:21652–21659. 2006. View Article : Google Scholar : PubMed/NCBI

22 

Doms RW, Lamb RA, Rose JK and Helenius A: Folding and assembly of viral membrane proteins. Virology. 193:545–562. 1993. View Article : Google Scholar : PubMed/NCBI

23 

Greif DM, Kou R and Michel T: Site-specific dephosphorylation of endothelial nitric oxide synthase by protein phosphatase 2A: evidence for crosstalk between phosphorylation sites. Biochemistry. 41:15845–15853. 2002. View Article : Google Scholar

24 

Millward TA, Zolnierowicz S and Hemmings BA: Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci. 24:186–191. 1999. View Article : Google Scholar : PubMed/NCBI

25 

Kaufman RJ: Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 13:1211–1233. 1999. View Article : Google Scholar : PubMed/NCBI

26 

Mehta JL, Li DY, Chen HJ, et al: Inhibition of LOX-1 by statins may relate to upregulation of eNOS. Biochem Biophys Res Commun. 289:857–861. 2001. View Article : Google Scholar : PubMed/NCBI

27 

Aoyama T, Sawamura T, Furutani Y, et al: Structure and chromosomal assignment of the human lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) gene. Biochem J. 339:177–184. 1999. View Article : Google Scholar : PubMed/NCBI

28 

Li D, Yang B and Mehta JL: Ox-LDL induces apoptosis in human coronary artery endothelial cells: role of PKC, PTK, bcl-2, and Fas. Am J Physiol. 275:H568–H576. 1998.PubMed/NCBI

29 

Li D and Mehta JL: Upregulation of endothelial receptor for oxidized LDL (LOX-1) by oxidized LDL and implications in apoptosis of human coronary artery endothelial cells: evidence from use of antisense LOX-1 mRNA and chemical inhibitors. Arterioscler Thromb Vasc Biol. 20:1116–1122. 2000. View Article : Google Scholar : PubMed/NCBI

30 

Oka K, Sawamura T, Kikuta K, et al: Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells. Proc Natl Acad Sci USA. 95:9535–9540. 1998. View Article : Google Scholar : PubMed/NCBI

31 

Mehta JL and Li DY: Identification and autoregulation of receptor for OX-LDL in cultured human coronary artery endothelial cells. Biochem Biophys Res Commun. 248:511–514. 1998. View Article : Google Scholar : PubMed/NCBI

32 

Shiojima I and Walsh K: Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res. 90:1243–1250. 2002. View Article : Google Scholar : PubMed/NCBI

33 

Wang X and Robbins J: Heart failure and protein quality control. Circ Res. 99:1315–1328. 2006. View Article : Google Scholar : PubMed/NCBI

34 

Glembotski CC: Endoplasmic reticulum stress in the heart. Circ Res. 101:975–984. 2007. View Article : Google Scholar

35 

Lai E, Teodoro T and Volchuk A: Endoplasmic reticulum stress: signaling the unfolded protein response. Physiology (Bethesda). 22:193–201. 2007. View Article : Google Scholar : PubMed/NCBI

36 

Schroder M and Kaufman RJ: The mammalian unfolded protein response. Annu Rev Biochem. 74:739–789. 2005. View Article : Google Scholar

37 

Yamaguchi H and Wang HG: CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem. 279:45495–45502. 2004. View Article : Google Scholar : PubMed/NCBI

38 

Ma Y, Brewer JW, Diehl JA and Hendershot LM: Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol. 318:1351–1365. 2002. View Article : Google Scholar : PubMed/NCBI

39 

Ron D and Habener JF: CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes Dev. 6:439–453. 1992. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Zhou J, Abid MD, Xiong Y, Chen Q and Chen J: ox-LDL downregulates eNOS activity via LOX-1-mediated endoplasmic reticulum stress. Int J Mol Med 32: 1442-1450, 2013.
APA
Zhou, J., Abid, M.D., Xiong, Y., Chen, Q., & Chen, J. (2013). ox-LDL downregulates eNOS activity via LOX-1-mediated endoplasmic reticulum stress. International Journal of Molecular Medicine, 32, 1442-1450. https://doi.org/10.3892/ijmm.2013.1513
MLA
Zhou, J., Abid, M. D., Xiong, Y., Chen, Q., Chen, J."ox-LDL downregulates eNOS activity via LOX-1-mediated endoplasmic reticulum stress". International Journal of Molecular Medicine 32.6 (2013): 1442-1450.
Chicago
Zhou, J., Abid, M. D., Xiong, Y., Chen, Q., Chen, J."ox-LDL downregulates eNOS activity via LOX-1-mediated endoplasmic reticulum stress". International Journal of Molecular Medicine 32, no. 6 (2013): 1442-1450. https://doi.org/10.3892/ijmm.2013.1513
Copy and paste a formatted citation
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Spandidos Publications style
Zhou J, Abid MD, Xiong Y, Chen Q and Chen J: ox-LDL downregulates eNOS activity via LOX-1-mediated endoplasmic reticulum stress. Int J Mol Med 32: 1442-1450, 2013.
APA
Zhou, J., Abid, M.D., Xiong, Y., Chen, Q., & Chen, J. (2013). ox-LDL downregulates eNOS activity via LOX-1-mediated endoplasmic reticulum stress. International Journal of Molecular Medicine, 32, 1442-1450. https://doi.org/10.3892/ijmm.2013.1513
MLA
Zhou, J., Abid, M. D., Xiong, Y., Chen, Q., Chen, J."ox-LDL downregulates eNOS activity via LOX-1-mediated endoplasmic reticulum stress". International Journal of Molecular Medicine 32.6 (2013): 1442-1450.
Chicago
Zhou, J., Abid, M. D., Xiong, Y., Chen, Q., Chen, J."ox-LDL downregulates eNOS activity via LOX-1-mediated endoplasmic reticulum stress". International Journal of Molecular Medicine 32, no. 6 (2013): 1442-1450. https://doi.org/10.3892/ijmm.2013.1513
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