, Volume 37, Issue 2, pp 365–372 | Cite as

Effects of resveratrol on NO secretion stimulated by insulin and its dependence on SIRT1 in high glucose cultured endothelial cells

  • Juhong Yang
  • Nan Wang
  • Jingyan Li
  • Jiaojiao Zhang
  • Ping Feng
Original Article


To investigate the effects of resveratrol on the secretion of NO induced by insulin in high glucose cultured primary human umbilical vein endothelial cells (HUVEC). HUVEC were treated with 1 μmol/l resveratrol for 24 h before cultured in high glucose medium for 48 h, then all cells were stimulated by 100 nmol/l insulin for 30 min. Method based on nitric acid reductase was used to analyze the NO contents in the supernatant. Cells were collected to analyze the expression of eNOS, endothelin-1, E-selectin, and SIRT1. In order to investigate the dependence of resveratrol on SIRT1, the effects of resveratrol on cells treated by SIRT1 siRNA were also examined. Compared with control cells, high glucose decreased the secretion of NO induced by insulin. Resveratrol treatment increased the expression of SIRT1 and the secretion of NO. After interfering the expression of SIRT1 using SIRT1 siRNA, the effects of resveratrol on the NO secretion induced by insulin was impaired. Resveratrol also counteracted other pro-atherosclerotic effects of high glucose, including the up-regulating roles of high glucose on the expression of endothelin-1 mRNA and E-selectin mRNA, and the down-regulating roles of high glucose on the expression of eNOS mRNA and the basal NO secretion without the stimulating of insulin. Resveratrol can improve the NO stimulating function of insulin in high glucose cultured HUVEC in SIRT1-dependent manner. Thus, our results imply that resveratrol may have the preventive roles of atherosclerosis in diabetic patients.


Resveratrol Endothelial cells SIRT1 High glucose Nitric oxide Atherosclerosis 


  1. 1.
    P.T. James, N. Rigby, R. Leach, The obesity epidemic, metabolic syndrome and future prevention strategies. Eur. J. Cardiovasc. Prev. Rehabil. 11, 3–8 (2004)CrossRefPubMedGoogle Scholar
  2. 2.
    R. Ross, Atherosclerosis—an inflammatory disease. N. Engl. J. Med. 340, 115–126 (1999)CrossRefPubMedGoogle Scholar
  3. 3.
    A.J. Hanley, K. Williams, M.P. Stern, S.M. Haffner, Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care 25, 1177–1184 (2002)CrossRefPubMedGoogle Scholar
  4. 4.
    J.A. Kim, M. Montagnani, K.K. Koh, M.J. Quon, Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 113, 1888–1904 (2006)CrossRefPubMedGoogle Scholar
  5. 5.
    R. Muniyappa, M. Montagnani, K.K. Koh et al., Cardiovascular actions of insulin. Endocr. Rev. 28, 463–491 (2007)CrossRefPubMedGoogle Scholar
  6. 6.
    M. Gronbaek, A. Deis, T.I. Sorensen, U. Becker, P. Schnohr, G. Jensen, Mortality associated with moderate intakes of wine, beer, or spirits. BMJ 310, 1165–1169 (1995)PubMedGoogle Scholar
  7. 7.
    M. Bohm, S. Rosenkranz, U. Laufs, Alcohol and red wine: impact on cardiovascular risk. Nephrol. Dial. Transplant. 19, 11–16 (2004)CrossRefPubMedGoogle Scholar
  8. 8.
    S. Renaud, M. de Lorgeril, Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 339, 1523–1526 (1992)CrossRefPubMedGoogle Scholar
  9. 9.
    B. Fuhrman, A. Lavy, M. Aviram, Consumption of red wine with meals reduces the susceptibility of human plasma and low-density lipoprotein to lipid peroxidation. Am. J. Clin. Nutr. 61, 549–554 (1995)PubMedGoogle Scholar
  10. 10.
    E.N. Frankel, A.L. Waterhouse, J.E. Kinsella, Inhibition of human LDL oxidation by resveratrol. Lancet 341, 1103–1104 (1993)CrossRefPubMedGoogle Scholar
  11. 11.
    H.S. Demrow, P.R. Slane, J.D. Folts, Administration of wine and grape juice inhibits in vivo platelet activity and thrombosis in stenosed canine coronary arteries. Circulation 91, 1182–1188 (1995)PubMedGoogle Scholar
  12. 12.
    F. Orsini, F. Pelizzoni, L. Verotta, T. Aburjai, C.B. Rogers, Isolation, synthesis, and antiplatelet aggregation activity of resveratrol 3-O-beta-D-glucopyranoside and related compounds. J. Nat. Prod. 60, 1082–1087 (1997)CrossRefPubMedGoogle Scholar
  13. 13.
    B. Olas, B. Wachowicz, J. Szewczuk, J. Saluk-Juszczak, W. Kaca, The effect of resveratrol on the platelet secretory process induced by endotoxin and thrombin. Microbios 105, 7–13 (2001)PubMedGoogle Scholar
  14. 14.
    K. Iijima, M. Yoshizumi, M. Hashimoto, S. Kim, M. Eto, J. Ako, Y.Q. Liang, N. Sudoh, K. Hosoda, K. Nakahara et al., Red wine polyphenols inhibit proliferation of vascular smooth muscle cells and downregulate expression of cyclin A gene. Circulation 101, 805–811 (2000)PubMedGoogle Scholar
  15. 15.
    K. Iijima, M. Yoshizumi, M. Hashimoto, M. Akishita, K. Kozaki, J. Ako, T. Watanabe, Y. Ohike, B. Son, J. Yu, K. Nakahara, Y. Ouchi, Red wine polyphenols inhibit vascular smooth muscle cell migration through two distinct signaling pathways. Circulation 105, 2404–2410 (2002)CrossRefPubMedGoogle Scholar
  16. 16.
    D.F. Fitzpatrick, S.L. Hirschfield, R.G. Coffey, Endothelium-dependent vasorelaxing activity of wine and other grape products. Am. J. Physiol. Heart Circ. Physiol. 265, H774–H778 (1993)Google Scholar
  17. 17.
    J. Lekakis, L.S. Rallidis, I. Andreadou, G. Vamvakou, G. Kazantzoglou, P. Magiatis, A.L. Skaltsounis, D.T. Kremastinos, Polyphenolic compounds from red grapes acutely improve endothelial function in patients with coronary heart disease. Eur. J. Cardiovasc. Prev. Rehabil. 12, 596–600 (2005)CrossRefPubMedGoogle Scholar
  18. 18.
    M. Ndiaye, M. Chataigneau, I. Lobysheva, T. Chataigneau, V.B. Schini-Kerth, Red wine polyphenol-induced, endothelium-dependent NO-mediated relaxation is due to the redox-sensitive PI3-kinase/Akt-dependent phosphorylation of endothelial NO-synthase in the isolated porcine coronary artery. FASEB J. 19, 455–457 (2005)PubMedGoogle Scholar
  19. 19.
    P. Cohen, The twentieth century struggle to decipher insulin signaling. Nat. Rev. Mol. Cell Biol. 7, 867–873 (2006)CrossRefPubMedGoogle Scholar
  20. 20.
    M. Jang, L. Cai, G.O. Udeani, K.V. Slowing, C.F. Thomas, C.W. Beecher, H.H. Fong, N.R. Farnsworth, A.D. Kinghorn, R.G. Methta, R.C. Moon, J.M. Pezzuto, Cancer chemoprotective activity of resveratrol, a natural product derived from grapes. Science 275, 218–220 (1997)CrossRefPubMedGoogle Scholar
  21. 21.
    D.S. Jang, B.S. Kang, S.Y. Ryu, I.M. Chang, K.R. Min, Y. Kim, Inhibitory effects of resveratrol analogs on unopsonized zymosan-induced oxygen radical production. Biochem. Pharmacol. 57, 705–712 (1999)CrossRefPubMedGoogle Scholar
  22. 22.
    M.I. Chung, C.M. Teng, K.L. Cheng, F.N. Ko, C.N. Lin, An antiplatelet principle of veratrum formosarum. Planta Med. 58, 274–276 (1992)CrossRefPubMedGoogle Scholar
  23. 23.
    E.H. Siemann, L.L. Creasy, Concentration of the phytoalexin resveratrol in wine. Am. J. Enol. Vitic. 43, 49–52 (1992)Google Scholar
  24. 24.
    S. Hui-Chen, H. Li-Man, C. Jan-Kan, Resveratrol, a red wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats. Resveratrol, a red wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats. Am. J. Physiol. Endocrinol. Metab. 290, E1339–E1346 (2006)CrossRefGoogle Scholar
  25. 25.
    C. Sun, F. Zhang, X. Ge et al., SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metab. 6, 307 (2007)CrossRefPubMedGoogle Scholar
  26. 26.
    Rutanen J, Yaluri N, Modi S et al., SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity. Diabetes (2010) [Epub ahead of print]Google Scholar
  27. 27.
    E.N. Frankel, J. Kanner, J.B. German et al., Inhibition of oxidation of human low density lipoprotein by phenolic substances in red wine. Lancet 341, 454–457 (1993)CrossRefPubMedGoogle Scholar
  28. 28.
    Q. Xu, X. Hao, Q. Yang et al., Resveratrol prevents hyperglycemia-induced endothelial dysfunction via activation of adenosine monophosphate-activated protein kinase. Biochem. Biophys. Res. Commun. 388, 389–394 (2009)CrossRefPubMedGoogle Scholar
  29. 29.
    F.L. Marasciulo, M. Montagnani, M.A. Potenza, Endothelin-1: the yin and yang on vascular function. Curr. Med. Chem. 13, 1655–1665 (2006)CrossRefPubMedGoogle Scholar
  30. 30.
    A. Hambrock, C.B. de Oliveira Franz, S. Hiller et al., Resveratrol binds to the sulfonylurea receptor (SUR) and induces apoptosis in a SUR subtype-specific manner. J. Biol. Chem. 282, 3347–3356 (2007)CrossRefPubMedGoogle Scholar
  31. 31.
    F. Picard, M. Kurtev, N. Chung et al., Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429, 771–776 (2004)CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Juhong Yang
    • 1
  • Nan Wang
    • 2
  • Jingyan Li
    • 3
  • Jiaojiao Zhang
    • 3
  • Ping Feng
    • 3
  1. 1.Metabolic Diseases HospitalTianjin Medical UniversityTianjinChina
  2. 2.Metabolism Department of Teda International Cardiovascular HospitalTianjin Medical UniversityTianjinChina
  3. 3.Metabolism Department of the General HospitalTianjin Medical UniversityTianjinChina

Personalised recommendations