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High glucose enhances store-operated calcium entry by upregulating ORAI/STIM via calcineurin-NFAT signalling

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Abstract

ORAI and stromal interaction molecule (STIM) are store-operated channel molecules that play essential roles in human physiology through a coupling mechanism of internal Ca2+ store to Ca2+ influx. However, the roles of ORAI and STIM in vascular endothelial cells under diabetic conditions remain unknown. Here, we investigated expression and signalling pathways of ORAI and STIM regulated by high glucose or hyperglycaemia using in vitro cell models, in vivo diabetic mice and tissues from patients. We found that ORAI1-3 and STIM1-2 were ubiquitously expressed in human vasculatures. Their expression was upregulated by chronic treatment with high glucose (HG, 25 mM d-glucose), which was accompanied by enhanced store-operated Ca2+ influx in vascular endothelial cells. The increased expression was also observed in the aortae from genetically modified Akita diabetic mice (C57BL/6-Ins2Akita/J) and streptozocin-induced diabetic mice, and aortae from diabetic patients. HG-induced upregulation of ORAI and STIM genes was prevented by the calcineurin inhibitor cyclosporin A and NFATc3 siRNA. Additionally, in vivo treatment with the nuclear factor of activated T cells (NFAT) inhibitor A-285222 prevented the gene upregulation in Akita mice. However, HG had no direct effects on ORAI1-3 currents and the channel activation process through cytosolic STIM1 movement in the cells co-expressing STIM1-EYFP/ORAIs. We concluded that upregulation of STIM/ORAI through Ca2+-calcineurin-NFAT pathway is a novel mechanism causing abnormal Ca2+ homeostasis and endothelial dysfunction under hyperglycaemia.

Key message

  • ORAI1-3 and STIM1-2 are ubiquitously expressed in vasculatures and upregulated by high glucose.

  • Increased expression is confirmed in Akita (Ins2Akita/J) and STZ diabetic mice and patients.

  • Upregulation mechanism is mediated by Ca2+/calcineurin/NFATc3 signalling.

  • High glucose has no direct effects on ORAI1-3 channel activity and channel activation process.

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References

  1. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS et al (2012) Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 125:e2–e220

    Article  PubMed  Google Scholar 

  2. Avogaro A, Albiero M, Menegazzo L, de Kreutzenberg S, Fadini GP (2011) Endothelial dysfunction in diabetes. Diabetes Care 34:S285–S290

    Article  PubMed Central  PubMed  Google Scholar 

  3. Kiselyov K, Shin DM, Muallem S (2003) Signalling specificity in GPCR-dependent Ca2+ signalling. Cell Signal 15:243–253

    Article  CAS  PubMed  Google Scholar 

  4. Parekh AB, Putney JW (2005) Store-operated calcium channels. Physiol Rev 85:757–810

    Article  CAS  PubMed  Google Scholar 

  5. Vig M, Peinelt C, Beck A, Koomoa DL, Rabah D, Koblan-Huberson M, Kraft S, Turner H, Fleig A, Penner R et al. (2006) CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 1127883. doi:10.1126/science.1127883

  6. Yeromin AV, Zhang SL, Jiang W, Yu Y, Safrina O, Cahalan MD (2006) Molecular identification of the CRAC channel by altered ion selectivity in a mutant of Orai. Nature 443: 226–229. doi http://www.nature.com/nature/journal/v443/n7108/suppinfo/nature05108_S1.html

  7. Xu SZ, Muraki K, Zeng F, Li J, Sukumar P, Shah S, Dedman AM, Flemming PK, McHugh D, Naylor J et al (2006) A sphingosine-1-phosphate-activated calcium channel controlling vascular smooth muscle cell motility. Circ Res 98:1381–1389

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Xu SZ, Boulay G, Flemming R, Beech DJ (2006) E3-targeted anti-TRPC5 antibody inhibits store-operated calcium entry in freshly isolated pial arterioles. Am J Physiol Heart Circ Physiol 291:H2653–H2659

    Article  CAS  PubMed  Google Scholar 

  9. Hogan PG, Lewis RS, Rao A (2010) Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu Rev Immunol 28:491–533

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Zhang SL (2005) STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437:902–905

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Lee KP, Yuan JP, So I, Worley PF, Muallem S (2010) STIM1-dependent and STIM1-independent function of transient receptor potential canonical (TRPC) channels tunes their store-operated mode. J Biol Chem 285:38666–38673

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Pani B, Ong HL, Brazer SC, Liu X, Rauser K, Singh BB, Ambudkar IS (2009) Activation of TRPC1 by STIM1 in ER-PM microdomains involves release of the channel from its scaffold caveolin-1. Proc Natl Acad Sci U S A 106:20087–20092

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Zeng B, Chen GL, Xu SZ (2012) Store-independent pathways for cytosolic STIM1 clustering in the regulation of store-operated Ca(2+) influx. Biochem Pharmacol 84:1024–1035

    Article  CAS  PubMed  Google Scholar 

  14. Tiruppathi C, Ahmmed GU, Vogel SM, Malik AB (2006) Ca2+ signaling, TRP channels, and endothelial permeability. Microcirculation 13:693–708

    Article  CAS  PubMed  Google Scholar 

  15. Abdullaev IF, Bisaillon JM, Potier M, Gonzalez JC, Motiani RK, Trebak M (2008) Stim1 and Orai1 mediate CRAC currents and store-operated calcium entry important for endothelial cell proliferation. Circ Res 103:1289–1299

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Li J, Cubbon RM, Wilson LA, Amer MS, McKeown L, Hou B, Majeed Y, Tumova S, Seymour VAL, Taylor H et al (2011) Orai1 and CRAC channel dependence of VEGF-activated Ca2+ entry and endothelial tube formation. Circ Res 108:1190–1198

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Mita M, Ito K, Taira K, Nakagawa J, Walsh MP, Shoji M (2010) Attenuation of store-operated Ca2+ entry and enhanced expression of TRPC channels in caudal artery smooth muscle from Type 2 diabetic Goto-Kakizaki rats. Clin Exp Pharmacol Physiol 37:670–678

    Article  CAS  PubMed  Google Scholar 

  18. Chung AW, Au Yeung K, Chum E, Okon EB, van Breemen C (2009) Diabetes modulates capacitative calcium entry and expression of transient receptor potential canonical channels in human saphenous vein. Eur J Pharmacol 613:114–118

    Article  CAS  PubMed  Google Scholar 

  19. Tamareille S, Mignen O, Capiod T, Rucker-Martin C, Feuvray D (2006) High glucose-induced apoptosis through store-operated calcium entry and calcineurin in human umbilical vein endothelial cells. Cell Calcium 39:47–55

    Article  CAS  PubMed  Google Scholar 

  20. Estrada IA, Donthamsetty R, Debski P, Zhou MH, Zhang SL, Yuan JX, Han W, Makino A (2012) STIM1 restores coronary endothelial function in type 1 diabetic mice. Circ Res 111:1166–1175

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Chaudhari S, Wu P, Wang Y, Ding Y, Yuan J, Begg M, Ma R (2014) High glucose and diabetes enhanced store-operated Ca2+ entry and increased expression of its signaling proteins in mesangial cells. Am J Physiol Ren Physiol. doi:10.1152/ajprenal.00463.2013

    Google Scholar 

  22. Nilsson-Berglund LM, Zetterqvist AV, Nilsson-Ohman J, Sigvardsson M, Gonzalez Bosc LV, Smith ML, Salehi A, Agardh E, Fredrikson GN, Agardh CD et al (2010) Nuclear factor of activated T cells regulates osteopontin expression in arterial smooth muscle in response to diabetes-induced hyperglycemia. Arterioscler Thromb Vasc Biol 30:218–224

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Xu SZ, Zhong W, Watson NM, Dickerson E, Wake JD, Lindow SW, Newton CJ, Atkin SL (2008) Fluvastatin reduces oxidative damage in human vascular endothelial cells by upregulating Bcl-2. J Thromb Haemost 6:692–700

    Article  CAS  PubMed  Google Scholar 

  24. Xu S-Z, Sukumar P, Zeng F, Li J, Jairaman A, English A, Naylor J, Ciurtin C, Majeed Y, Milligan CJ et al (2008) TRPC channel activation by extracellular thioredoxin. Nature 451:69–72

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Xu SZ, Zeng B, Daskoulidou N, Chen GL, Atkin SL, Lukhele B (2012) Activation of TRPC cationic channels by mercurial compounds confers the cytotoxicity of mercury exposure. Toxicol Sci 125:56–68

    Article  CAS  PubMed  Google Scholar 

  26. Nilsson LM, Nilsson-Ohman J, Zetterqvist AV, Gomez MF (2008) Nuclear factor of activated T-cells transcription factors in the vasculature: the good guys or the bad guys? Curr Opin Lipidol 19:483–490

    Article  CAS  PubMed  Google Scholar 

  27. Kimura C, Oike M, Ito Y (1998) Acute glucose overload abolishes Ca2+ oscillation in cultured endothelial cells from bovine aorta: a possible role of superoxide anion. Circ Res 82:677–685

    Article  CAS  PubMed  Google Scholar 

  28. Kimura C, Oike M, Kashiwagi S, Ito Y (1998) Effects of acute glucose overload on histamine H2 receptor-mediated Ca2+ mobilization in bovine cerebral endothelial cells. Diabetes 47:104–112

    Article  CAS  PubMed  Google Scholar 

  29. Pieper GM, Dondlinger LA (1998) Antioxidant pyrrolidine dithiocarbamate prevents defective bradykinin-stimulated calcium accumulation and nitric oxide activity following exposure of endothelial cells to elevated glucose concentration. Diabetologia 41:806–812

    Article  CAS  PubMed  Google Scholar 

  30. Graier WF, Wascher TC, Lackner L, Toplak H, Krejs GJ, Kukovetz WR (1993) Exposure to elevated D-glucose concentrations modulates vascular endothelial cell vasodilatory response. Diabetes 42:1497–1505

    Article  CAS  PubMed  Google Scholar 

  31. Paltauf-Doburzynska J, Malli R, Graier WF (2004) Hyperglycemic conditions affect shape and Ca2+ homeostasis of mitochondria in endothelial cells. J Cardiovasc Pharmacol 44:423–436

    Article  CAS  PubMed  Google Scholar 

  32. Liu D, Maier A, Scholze A, Rauch U, Boltzen U, Zhao Z, Zhu Z, Tepel M (2008) High glucose enhances transient receptor potential channel canonical type 6-dependent calcium influx in human platelets via phosphatidylinositol 3-kinase-dependent pathway. Arterioscler Thromb Vasc Biol 28:746–751

    Article  PubMed  Google Scholar 

  33. Bishara NB, Ding H (2010) Glucose enhances expression of TRPC1 and calcium entry in endothelial cells. Am J Physiol Heart Circ Physiol 298:H171–H178

    Article  CAS  PubMed  Google Scholar 

  34. Wuensch T, Thilo F, Krueger K, Scholze A, Ristow M, Tepel M (2010) High glucose-induced oxidative stress increases transient receptor potential channel expression in human monocytes. Diabetes 59:844–849

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Chen GL, Zeng B, Eastmond S, Elsenussi SE, Boa AN, Xu SZ (2012) Pharmacological comparison of novel synthetic fenamate analogues with econazole and 2-APB on the inhibition of TRPM2 channels. Br J Pharmacol 167:1232–1243

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Grupe M, Myers G, Penner R, Fleig A (2010) Activation of store-operated I(CRAC) by hydrogen peroxide. Cell Calcium 48:1–9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Graier WF, Simecek S, Hoebel BG, Wascher TC, Dittrich P, Kostner GM (1997) Antioxidants prevent high-D-glucose-enhanced endothelial Ca2+/cGMP response by scavenging superoxide anions. Eur J Pharmacol 322:113–122

    Article  CAS  PubMed  Google Scholar 

  38. Graham S, Ding M, Sours-Brothers S, Yorio T, Ma JX, Ma R (2007) Downregulation of TRPC6 protein expression by high glucose, a possible mechanism for the impaired Ca2+ signaling in glomerular mesangial cells in diabetes. Am J Physiol Ren Physiol 293:F1381–F1390

    Article  CAS  Google Scholar 

  39. Nutt LK, O'Neil RG (2000) Effect of elevated glucose on endothelin-induced store-operated and non-store-operated calcium influx in renal mesangial cells. J Am Soc Nephrol 11:1225–1235

    CAS  PubMed  Google Scholar 

  40. Zhang X, Zhang W, Gonzalez-Cobos JC, Jardin I, Romanin C, Matrougui K, Trebak M (2014) Complex role of STIM1 in the activation of store-independent Orai1/3 channels. J Gen Physiol 143:345–359

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Prof. A. V. Tepikin (University of Liverpool) for providing the STIM1-EYFP cDNA, Prof. D. J. Beech for comments on the manuscript and Dr. A. Green (University of Hull) for technical help. This work was supported in part by the British Heart Foundation and Leverhulme Trust (to S. Z. X.), University Ph.D. studentship (to N. D.), and China Scholarship Council (to B. Z.), and also by the Swedish Research Council (no. 2011-3900), Swedish Heart and Lung foundation, Albert Påhlsson and Diabetes foundations, and Innovative Medicines Initiative Joint Undertaking [no. 115006] comprising funds from the European Union’s Seventh Framework Programme [FP7/2007-2013] (to M. F. G.).

Conflict of interests

The authors state that they have no conflict of interest.

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Authors and Affiliations

  1. Centre for Cardiovascular and Metabolic Research, Hull York Medical School, University of Hull, Hull, HU6 7RX, UK

    Nikoleta Daskoulidou, Bo Zeng, Hongni Jiang, Gui-Lan Chen, James Ayoola & Shang-Zhong Xu

  2. Department of Clinical Sciences in Malmö, Lund University, Lund, Sweden

    Lisa M. Berglund, Olga Kotova & Maria F. Gomez

  3. Department of Renal Medicine and Hull York Medical School, Hull Royal Infirmary, Hull and East Yorkshire Hospitals NHS Trust, Hull, UK

    Sunil Bhandari

  4. Department of Cardiac Surgery, Castle Hill Hospital, Hull and East Yorkshire Hospitals NHS Trust, Hull, UK

    Steven Griffin

  5. Weill Cornell Medical College in Qatar, PO Box 24144, Doha, Qatar

    Stephen L. Atkin

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  1. Nikoleta Daskoulidou
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  2. Bo Zeng
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  3. Lisa M. Berglund
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  9. Steven Griffin
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  10. Stephen L. Atkin
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  11. Maria F. Gomez
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  12. Shang-Zhong Xu
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Corresponding author

Correspondence to Shang-Zhong Xu.

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Author’s contributions

N. Daskoulidou and S. Z. Xu designed the study. N. Daskoulidou, B. Zeng, H. Jiang and G. L. Chen performed the experiments. L. M. Berglund, O. Kotova and M. F. Gomez were responsible for diabetic mice models. S. Bhandari, J. Ayoola and S. Griffin collected clinical data and human tissue samples. S. Z. Xu, S. L. Atkin and M. F. Gomez conceived the study. S. Z. Xu and N. Daskoulidou wrote the manuscript. All the authors critically reviewed the manuscript.

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Daskoulidou, N., Zeng, B., Berglund, L.M. et al. High glucose enhances store-operated calcium entry by upregulating ORAI/STIM via calcineurin-NFAT signalling. J Mol Med 93, 511–521 (2015). https://doi.org/10.1007/s00109-014-1234-2

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  • DOI: https://doi.org/10.1007/s00109-014-1234-2

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