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Molecular Medicine

, Volume 17, Issue 9–10, pp 883–892 | Cite as

A Nonerythropoietic Peptide that Mimics the 3D Structure of Erythropoietin Reduces Organ Injury/Dysfunction and Inflammation in Experimental Hemorrhagic Shock

  • Nimesh S. A. Patel
  • Kiran K. Nandra
  • Michael Brines
  • Massimo Collino
  • W. S. Fred Wong
  • Amar Kapoor
  • Elisa Benetti
  • Fera Y. Goh
  • Roberto Fantozzi
  • Anthony Cerami
  • Christoph Thiemermann
Research Article

Abstract

Recent studies have shown that erythropoietin, critical for the differentiation and survival of erythrocytes, has cytoprotective effects in a wide variety of tissues, including the kidney and lung. However, erythropoietin has been shown to have a serious side effect—an increase in thrombovascular effects. We investigated whether pyroglutamate helix B-surface peptide (pHBSP), a nonerythropoietic tissue-protective peptide mimicking the 3D structure of erythropoietin, protects against the organ injury/dysfunction and inflammation in rats subjected to severe hemorrhagic shock (HS). Mean arterial blood pressure was reduced to 35 ± 5 mmHg for 90 min followed by resuscitation with 20 mL/kg Ringer Lactate for 10 min and 50% of the shed blood for 50 min. Rats were euthanized 4 h after the onset of resuscitation. pHBSP was administered 30 min or 60 min into resuscitation. HS resulted in significant organ injury/dysfunction (renal, hepatic, pancreas, neuromuscular, lung) and inflammation (lung). In rats subjected to HS, pHBSP significantly attenuated (i) organ injury/dysfunction (renal, hepatic, pancreas, neuromuscular, lung) and inflammation (lung), (ii) increased the phosphorylation of Akt, glycogen synthase kinase-3β and endothelial nitric oxide synthase, (iii) attenuated the activation of nuclear factor (nf)-κB and (iv) attenuated the increase in p38 and extracellular signal-regulated kinase (ERK)1/2 phosphorylation. pHBSP protects against multiple organ injury/dysfunction and inflammation caused by severe hemorrhagic shock by a mechanism that may involve activation of Akt and endothelial nitric oxide synthase, and inhibition of glycogen synthase kinase-3β and NF-κB.

Notes

Acknowledgments

NSAP is supported by a Kidney Research United Kingdom Post-Doctoral Fellowship (PDF4/2009). KKN is supported by a British Heart Foundation PhD Studentship (FS/10/57/28485). WSFW is supported, in part, by a Bio-Medical Research Council of Singapore Grant (09/1/21/19/595). This work is supported, in part, by the William Harvey Research Foundation. This work forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit which is supported and funded by the National Institute of Health Research.

References

  1. 1.
    Markovchick VJ, Moore EE. (2007) Optimal trauma outcome: trauma system design and the trauma team. Emerg. Med. Clin. North Am. 25:643–54, viii.CrossRefPubMedGoogle Scholar
  2. 2.
    Stewart RM, et al. (2003) Seven hundred fifty-three consecutive deaths in a level I trauma center: the argument for injury prevention. J. Trauma. 54:66–70; discussion 70–1.CrossRefPubMedGoogle Scholar
  3. 3.
    Sauaia A, et al. (1994) Early predictors of postinjury multiple organ failure. Arch. Surg. 129:39–45.CrossRefPubMedGoogle Scholar
  4. 4.
    Sambasivan CN, Schreiber MA. (2009) Emerging therapies in traumatic hemorrhage control. Curr. Opin. Crit. Care 15:560–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Konstantinopoulos PA, Karamouzis MV, Papavassiliou AG. (2007) Selective modulation of the erythropoietic and tissue-protective effects of erythropoietin: time to reach the full therapeutic potential of erythropoietin. Biochim. Biophys. Acta. 1776:1–9.PubMedGoogle Scholar
  6. 6.
    Brines M, Cerami A. (2006) Discovering erythropoietin’s extra-hematopoietic functions: biology and clinical promise. Kidney Int. 70:246–50.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Sepodes B, et al. (2006) Recombinant human erythropoietin protects the liver from hepatic ischemia-reperfusion injury in the rat. Transpl. Int. 19:919–26.CrossRefPubMedGoogle Scholar
  8. 8.
    Sharples EJ, et al. (2004) Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion. J. Am. Soc. Nephrol. 15:2115–24.CrossRefPubMedGoogle Scholar
  9. 9.
    Varet B, Casadevall N, Lacombe C, Nayeaux P. (1990) Erythropoietin: physiology and clinical experience. Semin. Hematol. 27:25–31.PubMedGoogle Scholar
  10. 10.
    Khorana AA, Francis CW, Culakova E, Lyman GH. (2005) Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study. Cancer. 104:2822–9.CrossRefGoogle Scholar
  11. 11.
    Napolitano LM, et al. (2008) Improved survival of critically ill trauma patients treated with recombinant human erythropoietin. J. Trauma. 65:285–97; discussion 297–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Brines M, et al. (2004) Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor. Proc. Natl. Acad. Sci. U. S. A. 101:14907–12.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Masuda S, et al. (1993) Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J. Biol. Chem. 268:11208–16.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Murphy JM, Young IG. (2006) IL-3, IL-5, and GM-CSF signaling: crystal structure of the human beta-common receptor. Vitam. Horm. 74:1–30.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Brines M, et al. (2008) Nonerythropoietic, tissue-protective peptides derived from the tertiary structure of erythropoietin. Proc. Natl. Acad. Sci. U. S. A. 105:10925–30.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Akinci OI, et al. (2005) Effects of body temperature on ventilator-induced lung injury. J. Crit. Care. 20:66–73.CrossRefPubMedGoogle Scholar
  17. 17.
    Collino M, et al. (2006) Oxidative stress and inflammatory response evoked by transient cerebral ischemia/reperfusion: effects of the PPAR-alpha agonist WY14643. Free Radic. Biol. Med. 41:579–89.CrossRefPubMedGoogle Scholar
  18. 18.
    Connelly KG, Repine JE. (1997) Markers for predicting the development of acute respiratory distress syndrome. Annu. Rev. Med. 48:429–45.CrossRefPubMedGoogle Scholar
  19. 19.
    Abdelrahman M, et al. (2004) Erythropoietin attenuates the tissue injury associated with hemorrhagic shock and myocardial ischemia. Shock. 22:63–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Lee JH, et al. (2007) Erythropoietin attenuates hyperoxia-induced lung injury by down-modulating inflammation in neonatal rats. J. Korean Med. Sci. 22:1042–7.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wu H, et al. (2006) Pretreatment with recombined human erythropoietin attenuates ischemia-reperfusion-induced lung injury in rats. Eur. J. Cardiothorac. Surg. 29:902–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Tascilar O, et al. (2007) Protective effects of erythropoietin against acute lung injury in a rat model of acute necrotizing pancreatitis. World J. Gastroenterol. 13:6172–82.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Burger D, Xenocostas A, Feng QP. (2009) Molecular basis of cardioprotection by erythropoietin. Curr. Mol. Pharmacol. 2:56–69.CrossRefPubMedGoogle Scholar
  24. 24.
    Fliser D, Bahlmann FH, Haller H. (2006) EPO: renoprotection beyond anemia correction. Pediatr. Nephrol. 21:1785–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Cantley LC. (2002) The phosphoinositide 3-kinase pathway. Science. 296:1655–7.CrossRefGoogle Scholar
  26. 26.
    Hanlon PR, et al. (2005) Mechanisms of erythro-poietin-mediated cardioprotection during ischemia-reperfusion injury: role of protein kinase C and phosphatidylinositol 3-kinase signaling. FASEB J. 19:1323–5.CrossRefPubMedGoogle Scholar
  27. 27.
    Hsu JT, et al. (2007) Mechanism of estrogen-mediated attenuation of hepatic injury following trauma-hemorrhage: Akt-dependent HO-1 upregulation. J. Leukoc. Biol. 82:1019–26.CrossRefPubMedGoogle Scholar
  28. 28.
    Ueba H, et al. (2010) Cardioprotection by a non-erythropoietic, tissue-protective peptide mimicking the 3D structure of erythropoietin. Proc. Natl. Acad. Sci. U. S. A. 107:14357–62.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 378:785–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Moule SK, et al. (1997) Regulation of protein kinase B and glycogen synthase kinase-3 by insulin and beta-adrenergic agonists in rat epididymal fat cells. Activation of protein kinase B by wortmannin-sensitive and -insensitive mechanisms. J. Biol. Chem. 272:7713–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Dugo L, et al. (2005) GSK-3beta inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat. Crit. Care Med. 33:1903–12.CrossRefPubMedGoogle Scholar
  32. 32.
    Nishihara M, et al. (2006) Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3 beta. Am. J. Physiol. Heart Circ. Physiol. 291:H748–55.CrossRefPubMedGoogle Scholar
  33. 33.
    Martin M, Rehani K, Jope RS, Michalek SM. (2005) Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat. Immunol. 6:777–84.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Collino M, et al. (2009) Insulin reduces cerebral ischemia/reperfusion injury in the hippocampus of diabetic rats: a role for glycogen synthase kinase-3beta. Diabetes. 58:235–42.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Wang Z, et al. (2010) GSK3beta promotes apoptosis after renal ischemic injury. J. Am. Soc. Nephrol. 21:284–94.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hoeflich KP, et al. (2000) Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature. 406:86–90.CrossRefGoogle Scholar
  37. 37.
    Takada Y, Fang X, Jamaluddin MS, Boyd DD, Aggarwal BB. (2004) Genetic deletion of glycogen synthase kinase-3beta abrogates activation of IkappaBalpha kinase, JNK, Akt, and p44/p42 MAPK but potentiates apoptosis induced by tumor necrosis factor. J. Biol. Chem. 279:39541–54.CrossRefPubMedGoogle Scholar
  38. 38.
    Dugo L, et al. (2006) Insulin reduces the multiple organ injury and dysfunction caused by coadministration of lipopolysaccharide and peptidoglycan independently of blood glucose: role of glycogen synthase kinase-3beta inhibition. Crit. Care Med. 34:1489–96.CrossRefPubMedGoogle Scholar
  39. 39.
    Senftleben U, Karin M. (2002) The IKK/NF-kappa B pathway. Crit. Care Med. 30:S18–26.CrossRefPubMedGoogle Scholar
  40. 40.
    Schwabe RF, Brenner DA. (2002) Role of glycogen synthase kinase-3 in TNF-alpha-induced NF-kappaB activation and apoptosis in hepatocytes. Am. J. Physiol. Gastrointest. Liver Physiol. 283:G204–211.CrossRefPubMedGoogle Scholar
  41. 41.
    Luque Contreras D, Vargas Robles H, Romo E, Rios A, Escalante B. (2006) The role of nitric oxide in the post-ischemic revascularization process. Pharmacol. Ther. 112:553–63.CrossRefPubMedGoogle Scholar
  42. 42.
    Anaya-Prado R, et al. (2003) The attenuation of hemorrhage-induced liver injury by exogenous nitric oxide, L-arginine, and inhibition of inducible nitric oxide synthase. J. Invest. Surg. 16:247–61.CrossRefPubMedGoogle Scholar
  43. 43.
    McDonald MC, Izumi M, Cuzzocrea S, Thiemermann C. (2002) A novel, potent and selective inhibitor of the activity of inducible nitric oxide synthase (GW274150) reduces the organ injury in hemorrhagic shock. J. Physiol. Pharmacol. 53:555–69.PubMedGoogle Scholar
  44. 44.
    Bullard AJ, Yellon DM. (2005) Chronic erythropoietin treatment limits infarct-size in the myocardium in vitro. Cardiovasc. Drugs Ther. 19:333–6.CrossRefPubMedGoogle Scholar
  45. 45.
    Su KH, et al. (2011) β common receptor integrates the erythropoietin signaling in activation of endothelial nitric oxide synthase. J. Cell. Physiol. 2011, Feb 14 [Epub ahead of print].Google Scholar
  46. 46.
    Donnahoo KK, Shames BD, Harken AH, Meldrum DR. (1999) Review article: the role of tumor necrosis factor in renal ischemia-reperfusion injury. J. Urol. 162:196–203.CrossRefPubMedGoogle Scholar
  47. 47.
    Guo X, Gerl RE, Schrader JW. (2003) Defining the involvement of p38alpha MAPK in the production of anti- and proinflammatory cytokines using an SB 203580-resistant form of the kinase. J. Biol. Chem. 278:22237–42.CrossRefPubMedGoogle Scholar
  48. 48.
    Sato H, Kasai K, Tanaka T, Kita T, Tanaka N. (2008) Role of tumor necrosis factor-alpha and interleukin-1beta on lung dysfunction following hemorrhagic shock in rats. Med. Sci. Monit. 14:BR79–87.PubMedGoogle Scholar
  49. 49.
    Sato H, Tanaka T, Kasai K, Kita T, Tanaka N. (2005) Role of p38 mitogen-activated protein kinase on renal dysfunction after hemorrhagic shock in rats. Shock. 24:488–94.CrossRefPubMedGoogle Scholar
  50. 50.
    Sato H, Tanaka T, Kasai K, Kita T, Tanaka N. (2007) Role of p38 mitogen-activated protein kinase on cardiac dysfunction after hemorrhagic shock in rats. Shock. 28:291–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Fukudome EY, et al. (2010) Pharmacologic resuscitation promotes survival and attenuates hemorrhage-induced activation of extracellular signalregulated kinase 1/2. J. Surg. Res. 163:118–126.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Valable S, et al. (2010) The impact of erythropoietin on short-term changes in phosphorylation of brain protein kinases in a rat model of traumatic brain injury. J. Cereb. Blood Flow Metab. 30:361–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Huang H, et al. (2009) Recombinant human erythropoietin protects against experimental spinal cord trauma injury by regulating expression of the proteins MKP-1 and p-ERK. J. Int. Med. Res. 37:511–9.CrossRefPubMedGoogle Scholar
  54. 54.
    Tyrrell DJ, Horne AP, Holme KR, Preuss JM, Page CP. (1999) Heparin in inflammation: potential therapeutic applications beyond anticoagulation. Adv. Pharmacol. 46:151–208.CrossRefPubMedGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011
www.feinsteininstitute.org

Authors and Affiliations

  • Nimesh S. A. Patel
    • 1
  • Kiran K. Nandra
    • 1
  • Michael Brines
    • 2
  • Massimo Collino
    • 3
  • W. S. Fred Wong
    • 4
  • Amar Kapoor
    • 1
  • Elisa Benetti
    • 3
  • Fera Y. Goh
    • 4
  • Roberto Fantozzi
    • 3
  • Anthony Cerami
    • 2
  • Christoph Thiemermann
    • 1
  1. 1.Barts and The London School of Medicine & Dentistry, William Harvey Research Institute, Centre for Translational Medicine and TherapeuticsQueen Mary University of LondonLondonUK
  2. 2.Araim PharmaceuticalsOssiningUSA
  3. 3.Department of Anatomy, Pharmacology and Forensic MedicineUniversity of TurinTurinItaly
  4. 4.Department of Pharmacology and Immunology ProgramNational University Health System, National University of SingaporeSingaporeSingapore

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