Inflammation

, Volume 40, Issue 2, pp 578–588 | Cite as

Protective Effects of Pterostilbene Against Myocardial Ischemia/Reperfusion Injury in Rats

  • Miao Wu
  • Shijuan Lu
  • Jianghua Zhong
  • Kang Huang
  • Saidan Zhang
ORIGINAL ARTICLE

Abstract

Pterostilbene (PTB) has been suggested to protect against myocardial ischemia/reperfusion (MI/R) injury. Gas6/Axl signaling has been suggested to play an important role in cell survival. However, the interaction between PTB and Gas6/Axl signaling in MI/R remains unclear. This study aims to evaluate the role of Gas6/Axl signaling in the protective effects of PTB against MI/R injury. In experiment 1, the rats were subjected to 30 min of ischemia, followed by 3, 6, and 12 h of reperfusion, respectively. In experiment 2, the rats were administered intraperitoneally with PTB or vehicle and subjected to MI/R injury. The results suggested that the expression of Gas6 and Axl decreased significantly after MI/R injury. PTB treatment conferred a cardioprotective effect with an improved post-ischemic cardiac function, a reduced myocardial infarct size, and decreased lactate dehydrogenase and creatine kinase-MB in the serum, a decreased oxidative stress and inflammation, and a reduced number of apoptotic cardiomyocytes. Moreover, PTB treatment up-regulated the expression of Gas6, Axl, and Bcl-2 and down-regulated Bax expression. Our findings suggest that PTB treatment exerts cardioprotection against MI/R injury via attenuating inflammatory response, oxidative stress, and apoptosis and up-regulating the expression of Gas6 and Axl. The application of PTB may be a new strategy for the treatment of MI/R injury.

KEY WORDS

pterostilbene myocardial ischemia/reperfusion injury Gas6/Axl signaling oxidative stress inflammation 

Notes

Compliance with Ethical Standards

Conflict of Interest

None declared.

References

  1. 1.
    Hausenloy, D.J., and D.M. Yellon. 2013. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. Journal of Clinical Investigation 123(1): 92–100. doi: 10.1172/JCI62874.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Bice, J.S., B.R. Jones, G.R. Chamberlain, and G.F. Baxter. 2016. Nitric oxide treatments as adjuncts to reperfusion in acute myocardial infarction: a systematic review of experimental and clinical studies. Basic Research in Cardiology 111(2): 23. doi: 10.1007/s00395-016-0540-y.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Petrosillo, G., F.M. Ruggiero, N. Di Venosa, and G. Paradies. 2003. Decreased complex III activity in mitochondria isolated from rat heart subjected to ischemia and reperfusion: role of reactive oxygen species and cardiolipin. FASEB Journal 17(6): 714–716. doi: 10.1096/fj.02-0729fje.PubMedGoogle Scholar
  4. 4.
    Csonka, C., M. Sarkozy, M. Pipicz, L. Dux, and T. Csont. 2016. Modulation of hypercholesterolemia-induced oxidative/nitrative stress in the heart. Oxidative Medicine and Cellular Longevity 2016: 3863726. doi: 10.1155/2016/3863726.CrossRefPubMedGoogle Scholar
  5. 5.
    Zweier, J.L., and M.A. Talukder. 2006. The role of oxidants and free radicals in reperfusion injury. Cardiovascular Research 70(2): 181–190. doi: 10.1016/j.cardiores.2006.02.025.CrossRefPubMedGoogle Scholar
  6. 6.
    Remsberg, C.M., J.A. Yanez, Y. Ohgami, K.R. Vega-Villa, A.M. Rimando, and N.M. Davies. 2008. Pharmacometrics of pterostilbene: preclinical pharmacokinetics and metabolism, anticancer, antiinflammatory, antioxidant and analgesic activity. Phytotherapy Research 22(2): 169–179. doi: 10.1002/ptr.2277.CrossRefPubMedGoogle Scholar
  7. 7.
    Cichocki, M., J. Paluszczak, H. Szaefer, A. Piechowiak, A.M. Rimando, and W. Baer-Dubowska. 2008. Pterostilbene is equally potent as resveratrol in inhibiting 12-O-tetradecanoylphorbol-13-acetate activated NFkappaB, AP-1, COX-2, and iNOS in mouse epidermis. Molecular Nutrition & Food Research 52(Suppl 1): S62–S70. doi: 10.1002/mnfr.200700466.Google Scholar
  8. 8.
    Kapetanovic, I.M., M. Muzzio, Z. Huang, T.N. Thompson, and D.L. McCormick. 2011. Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats. Cancer Chemotheraphy and Pharmacology 68(3): 593–601. doi: 10.1007/s00280-010-1525-4.CrossRefGoogle Scholar
  9. 9.
    Lv, M., K. Liu, S. Fu, Z. Li, and X. Yu. 2015. Pterostilbene attenuates the inflammatory reaction induced by ischemia/reperfusion in rat heart. Molecular Medicine Reports 11(1): 724–728. doi: 10.3892/mmr.2014.2719.PubMedGoogle Scholar
  10. 10.
    Park, E.S., Y. Lim, J.T. Hong, H.S. Yoo, C.K. Lee, M.Y. Pyo, and Y.P. Yun. 2010. Pterostilbene, a natural dimethylated analog of resveratrol, inhibits rat aortic vascular smooth muscle cell proliferation by blocking Akt-dependent pathway. Vascular Pharmacology 53(1–2): 61–67. doi: 10.1016/j.vph.2010.04.001.CrossRefPubMedGoogle Scholar
  11. 11.
    Schneider, C., R.M. King, and L. Philipson. 1988. Genes specifically expressed at growth arrest of mammalian cells. Cell 54(6): 787–793. doi: 10.1016/S0092-8674(88)91065-3.CrossRefPubMedGoogle Scholar
  12. 12.
    Wang, C., H. Jin, N. Wang, S. Fan, Y. Wang, Y. Zhang, L. Wei, et al. 2016. Gas6/Axl axis contributes to chemoresistance and metastasis in breast cancer through Akt/GSK-3beta/beta-catenin signaling. Theranostics 6(8): 1205–1219. doi: 10.7150/thno.15083.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Batchu, S.N., A. Hughson, J. Gerloff, D.J. Fowell, and V.A. Korshunov. 2013. Role of Axl in early kidney inflammation and progression of salt-dependent hypertension. Hypertension 62(2): 302–309. doi: 10.1161/HYPERTENSIONAHA.113.01382.CrossRefPubMedGoogle Scholar
  14. 14.
    Barcena, C., M. Stefanovic, A. Tutusaus, L. Joannas, A. Menendez, C. Garcia-Ruiz, P. Sancho-Bru, et al. 2015. Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. Journal of Hepatology 63(3): 670–678. doi: 10.1016/j.jhep.2015.04.013.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lijnen, H.R., V. Christiaens, and L. Scroyen. 2011. Growth arrest-specific protein 6 receptor antagonism impairs adipocyte differentiation and adipose tissue development in mice. Journal of Pharmacol and Experimental Therapeutics 337(2): 457–464. doi: 10.1124/jpet.110.178046.CrossRefGoogle Scholar
  16. 16.
    Llacuna, L., C. Barcena, L. Bellido-Martin, L. Fernandez, M. Stefanovic, M. Mari, C. Garcia-Ruiz, J.C. Fernandez-Checa, P. Garcia de Frutos, and A. Morales. 2010. Growth arrest-specific protein 6 is hepatoprotective against murine ischemia/reperfusion injury. Hepatology 52(4): 1371–1379. doi: 10.1002/hep.23833.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ji, L., F. Fu, L. Zhang, W. Liu, X. Cai, L. Zhang, Q. Zheng, H. Zhang, and F. Gao. 2010. Insulin attenuates myocardial ischemia/reperfusion injury via reducing oxidative/nitrative stress. American Journal of Physiology, Endocrinology and Metabolism 298(4): E871–E880. doi: 10.1152/ajpendo.00623.2009.CrossRefPubMedGoogle Scholar
  18. 18.
    Su, H., L. Ji, W. Xing, W. Zhang, H. Zhou, X. Qian, X. Wang, F. Gao, X. Sun, and H. Zhang. 2013. Acute hyperglycaemia enhances oxidative stress and aggravates myocardial ischaemia/reperfusion injury: role of thioredoxin-interacting protein. Journal of Cellular and Molecular Medicine 17(1): 181–191. doi: 10.1111/j.1582-4934.2012.01661.x.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Guo, Y., L. Zhang, F. Li, C.P. Hu, and Z. Zhang. 2016. Restoration of sirt1 function by pterostilbene attenuates hypoxia-reoxygenation injury in cardiomyocytes. European Journal of Pharmacology 776: 26–33. doi: 10.1016/j.ejphar.2016.02.052.CrossRefPubMedGoogle Scholar
  20. 20.
    Li, J., Ruzhi Deng, X. Hua, L. Zhang, F. Lu, T.G. Coursey, S.C. Pflugfelder, and D.Q. Li. 2016. Blueberry component pterostilbene protects corneal epithelial cells from inflammation via anti-oxidative pathway. Scientific Reports 6: 19408. doi: 10.1038/srep19408.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Perecko, T., K. Drabikova, A. Lojek, M. Ciz, S. Ponist, K. Bauerova, R. Nosal, J. Harmatha, and V. Jancinova. 2013. The effects of pterostilbene on neutrophil activity in experimental model of arthritis. BioMed Research International 2013: 106041. doi: 10.1155/2013/106041.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Qureshi, A.A., X.Q. Guan, J.C. Reis, C.J. Papasian, S. Jabre, D.C. Morrison, and N. Qureshi. 2012. Inhibition of nitric oxide and inflammatory cytokines in LPS-stimulated murine macrophages by resveratrol, a potent proteasome inhibitor. Lipids in Health and Disease 11: 76. doi: 10.1186/1476-511X-11-76.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Lin, J., H. Wang, J. Li, Q. Wang, S. Zhang, N. Feng, R. Fan, and J. Pei. 2013. kappa-Opioid receptor stimulation modulates TLR4/NF-kappaB signaling in the rat heart subjected to ischemia-reperfusion. Cytokine 61(3): 842–848. doi: 10.1016/j.cyto.2013.01.002.CrossRefPubMedGoogle Scholar
  24. 24.
    Tian, Y., H. Li, P. Liu, J.M. Xu, M.G. Irwin, Z. Xia, and G. Tian. 2015. Captopril pretreatment produces an additive cardioprotection to isoflurane preconditioning in attenuating myocardial ischemia reperfusion injury in rabbits and in humans. Mediators of Inflammation 2015: 819232. doi: 10.1155/2015/819232.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Neri, M., I. Riezzo, C. Pomara, S. Schiavone, and E. Turillazzi. 2016. Oxidative-nitrosative stress and myocardial dysfunctions in sepsis: evidence from the literature and postmortem observations. Mediators of Inflammation 2016: 3423450. doi: 10.1155/2016/3423450.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Bedard, K., and K.H. Krause. 2007. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiological Reviews 87(1): 245–313. doi: 10.1152/physrev.00044.2005.CrossRefPubMedGoogle Scholar
  27. 27.
    Seko, Y., T. Fujimura, T. Yao, H. Taka, R. Mineki, K. Okumura, and K. Murayama. 2015. Secreted tyrosine sulfated-eIF5A mediates oxidative stress-induced apoptosis. Scientific Reports 5: 13737. doi: 10.1038/srep13737.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Pei, H., Q. Yu, Q. Xue, Y. Guo, L. Sun, Z. Hong, H. Han, E. Gao, Y. Qu, and L. Tao. 2013. Notch1 cardioprotection in myocardial ischemia/reperfusion involves reduction of oxidative/nitrative stress. Basic Research in Cardiology 108(5): 373. doi: 10.1007/s00395-013-0373-x.CrossRefPubMedGoogle Scholar
  29. 29.
    Chen, Y.Q., J. Zhao, C.W. Jin, Y.H. Li, M.X. Tang, Z.H. Wang, W. Zhang, Y. Zhang, L. Li, and M. Zhong. 2016. Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway. Age (Dordrecht, Netherlands) 38(3): 60. doi: 10.1007/s11357-016-9910-5.CrossRefGoogle Scholar
  30. 30.
    Chen, L.W., W. Chen, Z.Q. Hu, J.L. Bian, L. Ying, G.L. Hong, Q.M. Qiu, G.J. Zhao, and Z.Q. Lu. 2016. Protective effects of growth arrest-specific protein 6 (Gas6) on sepsis-induced acute kidney injury. Inflammation 39(2): 575–582. doi: 10.1007/s10753-015-0282-2.CrossRefPubMedGoogle Scholar
  31. 31.
    Giangola, M.D., W.L. Yang, S.R. Rajayer, J. Nicastro, G.F. Coppa, and P. Wang. 2013. Growth arrest-specific protein 6 attenuates neutrophil migration and acute lung injury in sepsis. Shock 40(6): 485–491. doi: 10.1097/SHK.0b013e3182a588c1.CrossRefPubMedGoogle Scholar
  32. 32.
    Giangola, M.D., W.L. Yang, S.R. Rajayer, M. Kuncewitch, E. Molmenti, J. Nicastro, G.F. Coppa, and P. Wang. 2015. Growth arrest-specific protein 6 protects against renal ischemia-reperfusion injury. Journal of Surgical Research 199(2): 572–579. doi: 10.1016/j.jss.2015.05.049.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Zagorska, A., P.G. Traves, E.D. Lew, I. Dransfield, and G. Lemke. 2014. Diversification of TAM receptor tyrosine kinase function. Nature Immunology 15(10): 920–928. doi: 10.1038/ni.2986.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Rothlin, C.V., S. Ghosh, E.I. Zuniga, M.B. Oldstone, and G. Lemke. 2007. TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131(6): 1124–1136. doi: 10.1016/j.cell.2007.10.034.CrossRefPubMedGoogle Scholar
  35. 35.
    Kimura, A., T. Naka, T. Muta, O. Takeuchi, S. Akira, I. Kawase, and T. Kishimoto. 2005. Suppressor of cytokine signaling-1 selectively inhibits LPS-induced IL-6 production by regulating JAK-STAT. Proceedings of the National Academy of Sciences of the United States of America 102(47): 17089–17094. doi: 10.1073/pnas.0508517102.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Fenner, J.E., R. Starr, A.L. Cornish, J.G. Zhang, D. Metcalf, R.D. Schreiber, K. Sheehan, D.J. Hilton, W.S. Alexander, and P.J. Hertzog. 2006. Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nature Immunology 7(1): 33–39. doi: 10.1038/ni1287.CrossRefPubMedGoogle Scholar
  37. 37.
    Yoshimura, A., T. Naka, and M. Kubo. 2007. SOCS proteins, cytokine signalling and immune regulation. Nature Reviews Immunology 7(6): 454–465. doi: 10.1038/nri2093.CrossRefPubMedGoogle Scholar
  38. 38.
    van den Brand, B.T., S. Abdollahi-Roodsaz, E.A. Vermeij, M.B. Bennink, O.J. Arntz, C.V. Rothlin, W.B. van den Berg, and F.A. van de Loo. 2013. Therapeutic efficacy of Tyro3, Axl, and Mer tyrosine kinase agonists in collagen-induced arthritis. Arthritis and Rheumatism 65(3): 671–680. doi: 10.1002/art.37786.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Gruber, R.C., A.K. Ray, C.T. Johndrow, H. Guzik, D. Burek, P.G. de Frutos, and B. Shafit-Zagardo. 2014. Targeted GAS6 delivery to the CNS protects axons from damage during experimental autoimmune encephalomyelitis. The Journal of Neuroscience 34(49): 16320–16335. doi: 10.1523/JNEUROSCI.2449-14.2014.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Miao Wu
    • 1
    • 2
  • Shijuan Lu
    • 1
  • Jianghua Zhong
    • 1
  • Kang Huang
    • 1
  • Saidan Zhang
    • 2
  1. 1.Department of CardiologyHaikou People’s Hospital, Xiangya School of Medicine Affiliated Haikou Hospital, Central South UniversityHaikouPeople’s Republic of China
  2. 2.Department of CardiologyXiangya Hospital, Central South UniversityChangshaPeople’s Republic of China

Personalised recommendations