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TRAIL death receptor 4 signaling via lysosome fusion and membrane raft clustering in coronary arterial endothelial cells: evidence from ASM knockout mice

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Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor 4 (DR4), have been implicated in the development of endothelial dysfunction and atherosclerosis. However, the signaling mechanism mediating DR4 activation leading to endothelial injury remains unclear. We recently demonstrated that ceramide production via hydrolysis of membrane sphingomyelin by acid sphingomyelinase (ASM) results in membrane raft (MR) clustering and the formation of important redox signaling platforms, which play a crucial role in amplifying redox signaling in endothelial cells leading to endothelial dysfunction. The present study aims to investigate whether TRAIL triggers MR clustering via lysosome fusion and ASM activation, thereby conducting transmembrane redox signaling and changing endothelial function. Using confocal microscopy, we found that TRAIL induced MR clustering and co-localized with DR4 in coronary arterial endothelial cells (CAECs) isolated from wild-type (Smpd1 +/+) mice. Furthermore, TRAIL triggered ASM translocation, ceramide production, and NADPH oxidase aggregation in MR clusters in Smpd1 +/+ CAECs, whereas these observations were not found in Smpd1 −/− CAECs. Moreover, ASM deficiency reduced TRAIL-induced O2 −⋅ production in CAECs and abolished TRAIL-induced impairment on endothelium-dependent vasodilation in small resistance arteries. By measuring fluorescence resonance energy transfer, we found that Lamp-1 (lysosome membrane marker protein) and ganglioside GM1 (MR marker) were trafficking together in Smpd1 +/+ CAECs, which was absent in Smpd1 −/− CAECs. Consistently, fluorescence imaging of living cells with specific lysosome probes demonstrated that TRAIL-induced lysosome fusion with membrane was also absent in Smpd1 −/− CAECs. Taken together, these results suggest that ASM is essential for TRAIL-induced lysosomal trafficking, membrane fusion and formation of MR redox signaling platforms, which may play an important role in DR4-mediated redox signaling in CAECs and consequently endothelial dysfunction.

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References

  1. Schneider P, Bodmer JL, Thome M, Hofmann K, Holler N, Tschopp J (1997) Characterization of two receptors for TRAIL. FEBS Lett 416:329–334

    Article  PubMed  CAS  Google Scholar 

  2. Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI et al (1997) Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors. Science 277:818–821

    Article  PubMed  CAS  Google Scholar 

  3. Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, Dul E, Appelbaum ER, Eichman C, DiPrinzio R et al (1998) Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem 273:14363–14367

    Article  PubMed  CAS  Google Scholar 

  4. Secchiero P, Gonelli A, Carnevale E, Milani D, Pandolfi A, Zella D, Zauli G (2003) TRAIL promotes the survival and proliferation of primary human vascular endothelial cells by activating the Akt and ERK pathways. Circulation 107:2250–2256

    Article  PubMed  Google Scholar 

  5. Secchiero P, Corallini F, di Iasio MG, Gonelli A, Barbarotto E, Zauli G (2005) TRAIL counteracts the proadhesive activity of inflammatory cytokines in endothelial cells by down-modulating CCL8 and CXCL10 chemokine expression and release. Blood 105:3413–3419

    Article  PubMed  CAS  Google Scholar 

  6. Fossati S, Ghiso J, Rostagno A (2012) TRAIL death receptors DR4 and DR5 mediate cerebral microvascular endothelial cell apoptosis induced by oligomeric Alzheimer’s Abeta. Cell Death Dis 3:e321

    Article  PubMed  CAS  Google Scholar 

  7. Li JH, Kirkiles-Smith NC, McNiff JM, Pober JS (2003) TRAIL induces apoptosis and inflammatory gene expression in human endothelial cells. J Immunol 171:1526–1533

    PubMed  CAS  Google Scholar 

  8. Alladina SJ, Song JH, Davidge ST, Hao C, Easton AS (2005) TRAIL-induced apoptosis in human vascular endothelium is regulated by phosphatidylinositol 3-kinase/Akt through the short form of cellular FLIP and Bcl-2. J Vasc Res 42:337–347

    Article  PubMed  CAS  Google Scholar 

  9. Zhang Y, Li X, Becker KA, Gulbins E (2009) Ceramide-enriched membrane domains—structure and function. Biochim Biophys Acta 1788:178–183

    Article  PubMed  CAS  Google Scholar 

  10. Grassme H, Jekle A, Riehle A, Schwarz H, Berger J, Sandhoff K, Kolesnick R, Gulbins E (2001) CD95 signaling via ceramide-rich membrane rafts. J Biol Chem 276:20589–20596

    Article  PubMed  CAS  Google Scholar 

  11. Zhang AY, Yi F, Zhang G, Gulbins E, Li PL (2006) Lipid raft clustering and redox signaling platform formation in coronary arterial endothelial cells. Hypertension 47:74–80

    Article  PubMed  CAS  Google Scholar 

  12. Dupree JL, Pomicter AD (2010) Myelin, DIGs, and membrane rafts in the central nervous system. Prostaglandins Other Lipid Mediat 91:118–129

    Article  PubMed  CAS  Google Scholar 

  13. Natoli G, Costanzo A, Guido F, Moretti F, Levrero M (1998) Apoptotic, non-apoptotic, and anti-apoptotic pathways of tumor necrosis factor signalling. Biochem Pharmacol 56:915–920

    Article  PubMed  CAS  Google Scholar 

  14. Zhang AY, Yi F, Jin S, Xia M, Chen QZ, Gulbins E, Li PL (2007) Acid sphingomyelinase and its redox amplification in formation of lipid raft redox signaling platforms in endothelial cells. Antioxid Redox Sig 9:817–828

    Article  CAS  Google Scholar 

  15. Jin S, Zhang Y, Yi F, Li PL (2008) Critical role of lipid raft redox signaling platforms in endostatin-induced coronary endothelial dysfunction. Arterioscler Thromb Vasc Biol 28:485–490

    Article  PubMed  CAS  Google Scholar 

  16. Bao JX, Xia M, Poklis JL, Han WQ, Brimson C, Li PL (2010) Triggering role of acid sphingomyelinase in endothelial lysosome-membrane fusion and dysfunction in coronary arteries. Am J Physiol Heart Circ Physiol 298:H992–H1002

    Article  PubMed  CAS  Google Scholar 

  17. Bao JX, Jin S, Zhang F, Wang ZC, Li N, Li PL (2010) Activation of membrane NADPH oxidase associated with lysosome-targeted acid sphingomyelinase in coronary endothelial cells. Antioxid Redox Sig 12:703–712

    Article  CAS  Google Scholar 

  18. Dumitru CA, Gulbins E (2006) TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis. Oncogene 25:5612–5625

    Article  PubMed  CAS  Google Scholar 

  19. Teng B, Ansari HR, Oldenburg PJ, Schnermann J, Mustafa SJ (2006) Isolation and characterization of coronary endothelial and smooth muscle cells from A1 adenosine receptor-knockout mice. Am J Physiol Heart Circ Physiol 290:H1713–H1720

    Article  PubMed  CAS  Google Scholar 

  20. Li JM, Mullen AM, Shah AM (2001) Phenotypic properties and characteristics of superoxide production by mouse coronary microvascular endothelial cells. J Mol Cell Cardiol 33:1119–1131

    Article  PubMed  CAS  Google Scholar 

  21. Boini KM, Xia M, Li C, Zhang C, Payne LP, Abais JM, Poklis JL, Hylemon PB, Li PL (2011) Acid sphingomyelinase gene deficiency ameliorates the hyperhomocysteinemia-induced glomerular injury in mice. Am J Pathol 179:2210–2219

    Article  PubMed  CAS  Google Scholar 

  22. Jin S, Yi F, Zhang F, Poklis JL, Li PL (2008) Lysosomal targeting and trafficking of acid sphingomyelinase to lipid raft platforms in coronary endothelial cells. Arterioscler Thromb Vasc Biol 28:2056–2062

    Article  PubMed  CAS  Google Scholar 

  23. Zhang DX, Yi FX, Zou AP, Li PL (2002) Role of ceramide in TNF-alpha-induced impairment of endothelium-dependent vasorelaxation in coronary arteries. Am J Physiol Heart Circ Physiol 283:H1785–H1794

    PubMed  CAS  Google Scholar 

  24. Bellail AC, Tse MC, Song JH, Phuphanich S, Olson JJ, Sun SY, Hao C (2010) DR5-mediated DISC controls caspase-8 cleavage and initiation of apoptosis in human glioblastomas. J Cell Mol Med 14:1303–1317

    Article  PubMed  CAS  Google Scholar 

  25. Song JH, Tse MC, Bellail A, Phuphanich S, Khuri F, Kneteman NM, Hao C (2007) Lipid rafts and nonrafts mediate tumor necrosis factor related apoptosis-inducing ligand induced apoptotic and nonapoptotic signals in non small cell lung carcinoma cells. Cancer Res 67:6946–6955

    Article  PubMed  CAS  Google Scholar 

  26. Xu L, Qu X, Zhang Y, Hu X, Yang X, Hou K, Teng Y, Zhang J, Sada K, Liu Y (2009) Oxaliplatin enhances TRAIL-induced apoptosis in gastric cancer cells by CBL-regulated death receptor redistribution in lipid rafts. FEBS Lett 583:943–948

    Article  PubMed  CAS  Google Scholar 

  27. Rossin A, Derouet M, Abdel-Sater F, Hueber AO (2009) Palmitoylation of the TRAIL receptor DR4 confers an efficient TRAIL-induced cell death signalling. Biochem J 419:185–192

    Article  PubMed  CAS  Google Scholar 

  28. Goni FM, Alonso A (2000) Membrane fusion induced by phospholipase C and sphingomyelinases. Biosci Rep 20:443–463

    Article  PubMed  CAS  Google Scholar 

  29. Min Y, Shi J, Zhang Y, Liu S, Liu Y, Zheng D (2009) Death receptor 5-recruited raft components contributes to the sensitivity of Jurkat leukemia cell lines to TRAIL-induced cell death. IUBMB Life 61:261–267

    Article  PubMed  CAS  Google Scholar 

  30. Yang B, Rizzo V (2007) TNF-alpha potentiates protein-tyrosine nitration through activation of NADPH oxidase and eNOS localized in membrane rafts and caveolae of bovine aortic endothelial cells. Am J Physiol Heart Circ Physiol 292:H954–H962

    Article  PubMed  CAS  Google Scholar 

  31. Shao D, Segal AW, Dekker LV (2003) Lipid rafts determine efficiency of NADPH oxidase activation in neutrophils. FEBS Lett 550:101–106

    Article  PubMed  CAS  Google Scholar 

  32. Samhan-Arias AK, Garcia-Bereguiain MA, Martin-Romero FJ, Gutierrez-Merino C (2009) Clustering of plasma membrane-bound cytochrome b5 reductase within ‘lipid raft’ microdomains of the neuronal plasma membrane. Mol Cell Neurosci 40:14–26 D

    Article  PubMed  CAS  Google Scholar 

  33. Zauli G, Pandolfi A, Gonelli A, Di Pietro R, Guarnieri S, Ciabattoni G, Rana R, Vitale M, Secchiero P (2003) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) sequentially upregulates nitric oxide and prostanoid production in primary human endothelial cells. Circ Res 92:732–740

    Article  PubMed  CAS  Google Scholar 

  34. Di Pietro R, Mariggio MA, Guarnieri S, Sancilio S, Giardinelli A, Di Silvestre S, Consoli A, Zauli G, Pandolfi A (2006) Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) regulates endothelial nitric oxide synthase (eNOS) activity and its localization within the human vein endothelial cells (HUVEC) in culture. J Cell Biochem 97:782–794

    Article  PubMed  Google Scholar 

  35. Heylen E, Huang A, Sun D, Kaley G (2009) Nitric oxide-mediated dilation of arterioles to intraluminal administration of aldosterone. J Cardiovasc Pharmacol 54:535–542

    Article  PubMed  CAS  Google Scholar 

  36. Schramm M, Herz J, Haas A, Kronke M, Utermohlen O (2008) Acid sphingomyelinase is required for efficient phago-lysosomal fusion. Cell Microbiol 10:1839–1853

    Article  PubMed  CAS  Google Scholar 

  37. Utermohlen O, Herz J, Schramm M, Kronke M (2008) Fusogenicity of membranes: the impact of acid sphingomyelinase on innate immune responses. Immunobiology 213:307–314

    Article  PubMed  Google Scholar 

  38. Tam C, Idone V, Devlin C, Fernandes MC, Flannery A, He X, Schuchman E, Tabas I, Andrews NW (2010) Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. J Cell Biol 189:1027–1038

    Article  PubMed  CAS  Google Scholar 

  39. Herz J, Pardo J, Kashkar H, Schramm M, Kuzmenkina E, Bos E, Wiegmann K, Wallich R, Peters PJ, Herzig S et al (2009) Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes. Nat Immunol 10:761–768

    Article  PubMed  CAS  Google Scholar 

  40. Li X, Gulbins E, Zhang Y (2012) Oxidative stress triggers Ca-dependent lysosome trafficking and activation of acid sphingomyelinase. Cell Physiol Biochem 30:815–826

    Article  PubMed  CAS  Google Scholar 

  41. Yu C, Alterman M, Dobrowsky RT (2005) Ceramide displaces cholesterol from lipid rafts and decreases the association of the cholesterol binding protein caveolin-1. J Lipid Res 46:1678–1691

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

This study was supported by grants from the National Institutes of Health (HL-57244, HL-075316, and HL-091464).

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The authors declare no conflict of interests related to this study.

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Authors and Affiliations

  1. Department of Pharmacology & Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Xiang Li, Wei-Qing Han, Krishna M. Boini, Min Xia, Yang Zhang & Pin-Lan Li

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  1. Xiang Li
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  2. Wei-Qing Han
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  3. Krishna M. Boini
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  4. Min Xia
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  5. Yang Zhang
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Correspondence to Yang Zhang or Pin-Lan Li.

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Xiang Li and Wei-Qing Han contributed equally to this work.

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Li, X., Han, WQ., Boini, K.M. et al. TRAIL death receptor 4 signaling via lysosome fusion and membrane raft clustering in coronary arterial endothelial cells: evidence from ASM knockout mice. J Mol Med 91, 25–36 (2013). https://doi.org/10.1007/s00109-012-0968-y

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  • DOI: https://doi.org/10.1007/s00109-012-0968-y

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