Molecular and Cellular Biochemistry

, Volume 442, Issue 1–2, pp 73–80 | Cite as

Resveratrol attenuates high glucose-induced endothelial cell apoptosis via mediation of store-operated calcium entry

  • Ting Lu
  • Dayan Zhou
  • Pan Gao
  • Liangyi Si
  • Qiang XuEmail author


The aim of this study was to evaluate the influence of resveratrol on HG-induced calcium entry in islet microvascular (MS-1) endothelial cells. MS-1 cells were pretreated with resveratrol or 2-APB (an inhibitor of store-operated calcium entry) and then incubated with high glucose. Cell viability was determined using the cell counting kit-8 method. Reactive oxygen species, endothelial apoptosis, and NO production were detected by DHE probe, TUNEL detection, and nitrate reductase assay kit. Protein levels of SOCE were detected by western blotting. Pretreatment with resveratrol significantly attenuated HG-induced endothelial apoptosis and improved cell viability. However, pretreatment with resveratrol and 2-APB abolished this effect, suggesting that the attenuation of HG-induced apoptosis by resveratrol may be associated with SOCE. Subsequent analyses indicated that HG induced the SOCE-related proteins, including TRPC1, Orai1, and Stim1. These results suggest that resveratrol pretreatment is associated with relieved HG-induced endothelial apoptosis at least partly via inhibition of SOCE-related proteins.


Resveratrol Store-operated calcium entry (SOCE) Endothelial cells Apoptosis High glucose 



We thank Fang LI for technique assistance in measuring intracellular Ca2+. The study was supported by Chongqing characteristics of specialist construction funds.

Authors’ contributions

Qiang Xu conceived of the study. Ting Lu carried out cell culture and Western blotting analysis, participated in TUNEL staining, and measurement of intracellular Ca2+. Dayan Zhou performed the statistical analysis. Pan Gao drafted the manuscript. Liangyi Si participated in the design of the study. All authors contributed to and have approved the final manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

11010_2017_3194_MOESM1_ESM.tif (12.5 mb)
Supplemental Fig. 1 Scheme image of the signaling mechanisms underlying inhibitory effect of resveratrol for high glucose-induced endothelial cell apoptosis via mediation of store-operated calcium entry. Calcium ion receptor (Stim1), which locates in the endoplasmic reticulum, was found to form Ca2+ channel with Orai1 when the TG was induced to release Ca2+ from the endoplasmic reticulum. High-glucose stimulates apoptosis of endothelial cells via induction of calcium influx through the activation of the SOC channel. Resveratrol functions via inhibiting the activation of the SOC channel to reduce calcium influx, and also via reducing the high glucose-induced reactive oxygen species generation, thereby reducing endothelial cell apoptosis. Supplementary material 1 (TIFF 12837 kb)


  1. 1.
    Mylroie H, Dumont O, Bauer A, Thornton CC, Mackey J, Calay D, Hamdulay SS, Choo JR, Boyle JJ, Samarel AM (2015) PKCε-CREB-Nrf2 signalling induces HO-1 in the vascular endothelium and enhances resistance to inflammation and apoptosis. Cardiovasc Res 106:509–519CrossRefGoogle Scholar
  2. 2.
    Liu ML, Williams KJ (2012) Microvesicles: potential markers and mediators of endothelial dysfunction. Curr Opin Endocrinol Diabetes Obes 19:121–127CrossRefGoogle Scholar
  3. 3.
    Rautou P-E, Vion A-C, Amabile N, Chironi G, Simon A, Tedgui A, Boulanger CM (2011) Microparticles, vascular function, and atherothrombosis. Circ Res 109:593–606CrossRefGoogle Scholar
  4. 4.
    Bornfeldt KE (2014) 2013 Russell Ross memorial lecture in vascular biology: cellular and molecular mechanisms of diabetes mellitus-accelerated atherosclerosis. Arterioscler Thromb Vasc Biol 34:705–714CrossRefGoogle Scholar
  5. 5.
    Chait A, Bornfeldt KE (2009) Diabetes and atherosclerosis: is there a role for hyperglycemia? J Lipid Res 50(Suppl):S335CrossRefGoogle Scholar
  6. 6.
    Hayashi T, Yamaguchi T, Sakakibara Y, Taguchi K, Maeda M, Kuzuya M, Hattori Y (2014) eNOS-dependent antisenscence effect of a calcium channel blocker in human endothelial cells. PLoS ONE 9:e88391CrossRefGoogle Scholar
  7. 7.
    Risso A, Mercuri F, Quagliaro L, Damante G, Ceriello A (2001) Intermittent high glucose enhances apoptosis in human umbilical vein endothelial cells in culture. Am J Physiol Endocrinol Metab 281:E924CrossRefGoogle Scholar
  8. 8.
    Quagliaro L, Piconi L, Assaloni R, Martinelli L, Motz E, Ceriello A (2003) Intermittent high glucose enhances apoptosis related to oxidative stress in human umbilical vein endothelial cells the role of protein kinase C and NAD(P)H-oxidase activation. Diabetes 52:2795–2804CrossRefGoogle Scholar
  9. 9.
    Takeuchi A, Kim B, Matsuoka S (2013) The mitochondrial Na+-Ca2+ exchanger, NCLX, regulates automaticity of HL-1 cardiomyocytes. Sci Rep 3:2766CrossRefGoogle Scholar
  10. 10.
    Muik M, Schindl R, Fahrner M, Romanin C (2012) Ca2+ release-activated Ca2+ (CRAC) current, structure, and function. Cell Mol Life Sci 69:4163–4176CrossRefGoogle Scholar
  11. 11.
    Murphy MP (2012) Modulating mitochondrial intracellular location as a redox signal. Sci Signal 5:39CrossRefGoogle Scholar
  12. 12.
    Zhang M, Song J-N, Wu Y, Zhao Y-L, Pang H-G, Fu Z-F, Zhang B-F, Ma X-D (2014) Suppression of STIM1 in the early stage after global ischemia attenuates the injury of delayed neuronal death by inhibiting store-operated calcium entry-induced apoptosis in rats. NeuroReport 25:507–513PubMedGoogle Scholar
  13. 13.
    Rao W, Zhang L, Su N, Wang K, Hui H, Wang L, Chen T, Luo P, Y-f Yang, Z-b Liu (2013) Blockade of SOCE protects HT22 cells from hydrogen peroxide-induced apoptosis. Biochem Biophys Res Commun 441:351–356CrossRefGoogle Scholar
  14. 14.
    Liu H, Jia X, Luo Z, Guan H, Jiang H, Li X, Yan M (2012) Inhibition of store-operated Ca2+ channels prevent ethanol-induced intracellular Ca2+ increase and cell injury in a human hepatoma cell line. Toxicol Lett 208:254–261CrossRefGoogle Scholar
  15. 15.
    Li W, Zhang M, Xu L, Lin D, Cai S, Zou F (2013) The apoptosis of non-small cell lung cancer induced by cisplatin through modulation of STIM1. Exp Toxicol Pathol 65:1073–1081CrossRefGoogle Scholar
  16. 16.
    Schmidt S, Liu G, Liu G, Yang W, Honisch S, Pantelakos S, Stournaras C, Hönig A, Lang F (2014) Enhanced Orai1 and STIM1 expression as well as store operated Ca2+ entry in therapy resistant ovary carcinoma cells. Oncotarget 5:4799–4810CrossRefGoogle Scholar
  17. 17.
    R-w Guo, L-x Yang, M-q Li, X-h Pan, Liu B, Y-l Deng (2012) Stim1-and Orai1-mediated store-operated calcium entry is critical for angiotensin II-induced vascular smooth muscle cell proliferation. Cardiovasc Res 93:360–370CrossRefGoogle Scholar
  18. 18.
    Guo R-W, Wang H, Gao P, Li M-Q, Zeng C-Y, Yu Y, Chen J-F, Song M-B, Shi Y-K, Huang L (2008) An essential role for stromal interaction molecule 1 in neointima formation following arterial injury. Cardiovasc Res 81(4):660–668CrossRefGoogle Scholar
  19. 19.
    Taguchi K, Hida M, Matsumoto T, Kobayashi T (2015) Resveratrol ameliorates clonidine-induced endothelium-dependent relaxation involving Akt and endothelial nitric oxide synthase regulation in type 2 diabetic mice. Biol Pharm Bull 38:1864–1872CrossRefGoogle Scholar
  20. 20.
    Selvaraj S, Sun Y, Sukumaran P, Singh BB (2015) Resveratrol activates autophagic cell death in prostate cancer cells via downregulation of STIM1 and the mTOR pathway. Mol CarcinogGoogle Scholar
  21. 21.
    Saul S, Stanisz H, Backes CS, Schwarz EC, Hoth M (2014) How ORAI and TRP channels interfere with each other: interaction models and examples from the immune system and the skin. Eur J Pharmacol 739:49–59CrossRefGoogle Scholar
  22. 22.
    Safi SZ, Qvist R, Yan GOS, Ismail ISB (2014) Differential expression and role of hyperglycemia induced oxidative stress in epigenetic regulation of β1, β2 and β3-adrenergic receptors in retinal endothelial cells. BMC Med Genomics 7:29CrossRefGoogle Scholar
  23. 23.
    Scheen AJ, Esser N, Paquot N (2015) Antidiabetic agents: potential anti-inflammatory activity beyond glucose control. Diabetes Metab 41:183–194CrossRefGoogle Scholar
  24. 24.
    Zhang Y, Qin W, Zhang L, Wu X, Du N, Hu Y, Li X, Shen N, Xiao D, Zhang H (2015) MicroRNA-26a prevents endothelial cell apoptosis by directly targeting TRPC6 in the setting of atherosclerosis. Sci Rep 5:9401CrossRefGoogle Scholar
  25. 25.
    Sun Y, Cui X, Wang J, Wu S, Bai Y, Wang Y, Wang B, Fang J (2015) Stromal interaction molecule 1 (STIM1) silencing inhibits tumor growth and promotes cell cycle arrest and apoptosis in hypopharyngeal carcinoma. Med Oncol 32:608Google Scholar
  26. 26.
    Raphaël M, Lehen’Kyi V, Vandenberghe M, Beck B, Khalimonchyk S, Vanden AF, Farsetti L, Germain E, Bokhobza A, Mihalache A (2014) TRPV6 calcium channel translocates to the plasma membrane via Orai1-mediated mechanism and controls cancer cell survival. Proc Natl Acad Sci USA 111:3870–3879CrossRefGoogle Scholar
  27. 27.
    Liu H, Hughes JD, Rollins S, Chen B, Perkins E (2011) Calcium entry via ORAI1 regulates glioblastoma cell proliferation and apoptosis. Exp Mol Pathol 91:753CrossRefGoogle Scholar
  28. 28.
    Casas-Rua V, Alvarez IS, Pozo-Guisado E, Martín-Romero FJ (2013) Inhibition of STIM1 phosphorylation underlies resveratrol-induced inhibition of store-operated calcium entry. Biochem Pharmacol 86:1555–1563CrossRefGoogle Scholar
  29. 29.
    Collins HE, Zhu-Mauldin X, Marchase RB, Chatham JC (2013) STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology. Am J Physiol Heart Circ Physiol 305:446–458CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Ting Lu
    • 1
  • Dayan Zhou
    • 1
  • Pan Gao
    • 2
  • Liangyi Si
    • 3
  • Qiang Xu
    • 1
    Email author
  1. 1.Department of CardiologyChongqing Fifth People ‘s HospitalChongqingChina
  2. 2.Department of GeriatricsThe First Affiliated Hospital of the Third Military Medical UniversityChongqingChina
  3. 3.Chongqing Medical University, Third Affiliated HospitalChongqingChina

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