Advertisement

Dual Behavior of Exosomes in Septic Cardiomyopathy

  • Valter Vinícius Silva Monteiro
  • Jordano Ferreira Reis
  • Rafaelli de Souza Gomes
  • Kely Campos Navegantes
  • Marta Chagas MonteiroEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 998)

Abstract

Sepsis is one of the main causes of ICU hospitalization worldwide, with a high mortality rate, and is associated with a large number of comorbidities. One of the main comorbidities associated with sepsis is septic cardiomyopathy. This process occurs mainly due to mechanisms of damage in the cardiovascular system that will lead to changes in cardiovascular physiology, such as decreased Ca2+ response, mitochondrial dysfunction and decreased β-adrenergic receptor response. Within this process the exosomes play an important role in the pathophysiology of this disease, in which the exosomal content is related to mechanisms that will trigger its development. After platelet activation through ROS exposition, exosomes containing high concentrations of NADPH are released in heart blood vessels, those exosomes will be internalized in endothelial cells leading to cell death and cardiac dysfunction. On the opposite, exosomes derived from mesenchymal stem cells contain miR-223, that have anti-inflammatory properties, are released in less quantities in septic patients causing an imbalance that leads to cardiac dysfunction.

Keywords

Septic cardiomyopathy Sepsis Exosome 

Notes

Conflicts of Interest

The authors declare no conflicts of interest in relation to this article.

References

  1. 1.
    Dellinger R, Levy M, Rhodes A (2013) Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care 41(2):580–637Google Scholar
  2. 2.
    Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche J-D, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent J-L, Angus DC (2016) The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315(8):801–810PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Dombrovskiy VY, Martin AA, Sunderram J, Paz HL (2007) Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med 35(5):1244–1250PubMedCrossRefGoogle Scholar
  4. 4.
    Remick DG (2007) Pathophysiology of sepsis. Am J Pathol 170(5):1435–1444PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Fallach R, Shainberg A, Avlas O, Fainblut M, Chepurko Y, Porat E, Hochhauser E (2010) Cardiomyocyte Toll-like receptor 4 is involved in heart dysfunction following septic shock or myocardial ischemia. J Mol Cell Cardiol 48(6):1236–1244PubMedCrossRefGoogle Scholar
  6. 6.
    Boomer JS, Green JM, Hotchkiss RS (2014) The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer? Virulence 5(1):45–56PubMedCrossRefGoogle Scholar
  7. 7.
    Jacobi J (2002) Pathophysiology of sepsis. Am J Health Syst Pharm 59(Suppl 1):S3–S8PubMedGoogle Scholar
  8. 8.
    Turner MD, Nedjai B, Hurst T, Pennington DJ (2014) Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim Biophys Acta, Mol Cell Res 1843(11):2563–2582PubMedCrossRefGoogle Scholar
  9. 9.
    Abraham E (2003) Nuclear factor-kappaB and its role in sepsis-associated organ failure. J Infect Dis 187(Suppl):S364–S369PubMedCrossRefGoogle Scholar
  10. 10.
    Nakae H, Motoyama S, Kurosawa S, Inaba H (1999) The effective removal of proinflammatory cytokines by continuous hemofiltration with a polymethylmethacrylate membrane following severe burn injury: report of three cases. Surg Today 29(8):762–765PubMedCrossRefGoogle Scholar
  11. 11.
    Shimaoka M, Park EJ (2008) Advances in understanding sepsis. Eur J Anaesthesiol Suppl 42:146–153PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    de Oliveira S, Rosowski EE, Huttenlocher A (2016) Neutrophil migration in infection and wound repair: going forward in reverse. Nat Rev Immunol 16(6):378–391PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Drifte G, Dunn-Siegrist I, Tissieres P, Pugin J (2013) Innate immune functions of immature neutrophils in patients with sepsis and severe systemic inflammatory response syndrome. Crit Care Med 41(3):820–832PubMedCrossRefGoogle Scholar
  14. 14.
    Bhagat K (1998) Endothelial function and myocardial infarction. Cardiovasc Res 39(2):312–317PubMedCrossRefGoogle Scholar
  15. 15.
    Szent-Gyorgyi AG (1975) Calcium regulation of muscle contraction. Biophys J 15(7):707–723PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Wakabayashi T (2015) Mechanism of the calcium-regulation of muscle contraction—in pursuit of its structural basis. Proc Jpn Acad Ser B Phys Biol Sci 91(7):321–350PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Tavernier B, Li JM, El-Omar MM, Lanone S, Yang ZK, Trayer IP, Mebazaa A, Shah AM (2001) Cardiac contractile impairment associated with increased phosphorylation of troponin I in endotoxemic rats. FASEB J 15(2):294–296PubMedGoogle Scholar
  18. 18.
    Abi-Gerges N, Tavernier B, Mebazaa A, Faivre V, Paqueron X, Payen D, Fischmeister R, Mery PF (1999) Sequential changes in autonomic regulation of cardiac myocytes after in vivo endotoxin injection in rat. Am J Respir Crit Care Med 160(4):1196–1204PubMedCrossRefGoogle Scholar
  19. 19.
    Liu S, Schreur KD (1995) G protein-mediated suppression of L-type Ca2+ current by interleukin-1 beta in cultured rat ventricular myocytes. Am J Phys 268(2 Pt 1):C339–C349Google Scholar
  20. 20.
    Tsai T-Y, Lou S-L, Wong K-L, Wang M-L, Su T-H, Liu Z-M, Yeh L-J, Chan P, Gong C-L, Leung Y-M (2015) Suppression of Ca(2+) influx in endotoxin-treated mouse cerebral cortex endothelial bEND.3 cells. Eur J Pharmacol 755:80–87PubMedCrossRefGoogle Scholar
  21. 21.
    Zhong J, Hwang TC, Adams HR, Rubin LJ (1997) Reduced L-type calcium current in ventricular myocytes from endotoxemic guinea pigs. Am J Phys 273(5 Pt 2):H2312–H2324Google Scholar
  22. 22.
    Wu LL, Liu MS (1992) Altered ryanodine receptor of canine cardiac sarcoplasmic reticulum and its underlying mechanism in endotoxin shock. J Surg Res 53(1):82–90PubMedCrossRefGoogle Scholar
  23. 23.
    Zhu X, Bernecker OY, Manohar NS, Hajjar RJ, Hellman J, Ichinose F, Valdivia HH, Schmidt U (2005) Increased leakage of sarcoplasmic reticulum Ca2+ contributes to abnormal myocyte Ca2+ handling and shortening in sepsis. Crit Care Med 33(3):598–604PubMedCrossRefGoogle Scholar
  24. 24.
    Ayers L, Nieuwland R, Kohler M, Kraenkel N, Ferry B, Leeson P (2015) Dynamic microvesicle release and clearance within the cardiovascular system: triggers and mechanisms. Clin Sci (Lond) 129(11):915–931CrossRefGoogle Scholar
  25. 25.
    Dai D-F, Rabinovitch PS, Ungvari Z (2012) Mitochondria and cardiovascular aging. Circ Res 110(8):1109–1124PubMedCrossRefGoogle Scholar
  26. 26.
    Marzetti E, Csiszar A, Dutta D, Balagopal G, Calvani R, Leeuwenburgh C (2013) Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics. Am J Phys Heart Circ Phys 305(4):H459–H476Google Scholar
  27. 27.
    Giustarini D, Dalle-Donne I, Tsikas D, Rossi R (2009) Oxidative stress and human diseases: origin, link, measurement, mechanisms, and biomarkers. Crit Rev Clin Lab Sci 46(5–6):241–281PubMedCrossRefGoogle Scholar
  28. 28.
    Reis JF, Monteiro VVS, de Souza Gomes R, do Carmo MM, da Costa GV, Ribera PC, Monteiro MC (2016) Action mechanism and cardiovascular effect of anthocyanins: a systematic review of animal and human studies. J Transl Med 14(1):315–315PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Sawyer DB, Colucci WS (2000) Mitochondrial oxidative stress in heart failure. Circ Res 86(2):119–121PubMedCrossRefGoogle Scholar
  30. 30.
    Singer M (2014) The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 5(1):66–72PubMedCrossRefGoogle Scholar
  31. 31.
    Cimolai MC, Alvarez S, Bode C, Bugger H (2015) Mitochondrial mechanisms in septic cardiomyopathy. Int J Mol Sci 16(8):17763–17778PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Wachter SB, Gilbert EM (2012) Beta-adrenergic receptors, from their discovery and characterization through their manipulation to beneficial clinical application. Cardiology 122(2):104–112PubMedCrossRefGoogle Scholar
  33. 33.
    Johnson M (2006) Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol 117(1):18–24. Quiz 25PubMedCrossRefGoogle Scholar
  34. 34.
    Strosberg AD (1993) Structure, function, and regulation of adrenergic receptors. Protein Sci 2(8):1198–1209PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Hahn PY, Wang P, Tait SM, Ba ZF, Reich SS, Chaudry IH (1995) Sustained elevation in circulating catecholamine levels during polymicrobial sepsis. Shock 4(4):269–273PubMedCrossRefGoogle Scholar
  36. 36.
    Reithmann C, Hallstrom S, Pilz G, Kapsner T, Schlag G, Werdan K (1993) Desensitization of rat cardiomyocyte adenylyl cyclase stimulation by plasma of noradrenaline-treated patients with septic shock. Circ Shock 41(1):48–59PubMedGoogle Scholar
  37. 37.
    Matsuda N, Hattori Y, Akaishi Y, Suzuki Y, Kemmotsu O, Gando S (2000) Impairment of cardiac beta-adrenoceptor cellular signaling by decreased expression of G(s alpha) in septic rabbits. Anesthesiology 93(6):1465–1473PubMedCrossRefGoogle Scholar
  38. 38.
    Wu L-L, Yang S-L, Yang R-C, Hsu H-K, Hsu C, Dong L-W, Liu M-S (2003) G protein and adenylate cyclase complex-mediated signal transduction in the rat heart during sepsis. Shock 19(6):533–537PubMedCrossRefGoogle Scholar
  39. 39.
    Gilbert EM, Olsen SL, Renlund DG, Bristow MR (1993) beta-Adrenergic receptor regulation and left ventricular function in idiopathic dilated cardiomyopathy. Am J Cardiol 71(9):23C–29CPubMedCrossRefGoogle Scholar
  40. 40.
    Boyd JH, Mathur S, Wang Y, Bateman RM, Walley KR (2006) Toll-like receptor stimulation in cardiomyoctes decreases contractility and initiates an NF-kappaB dependent inflammatory response. Cardiovasc Res 72(3):384–393PubMedCrossRefGoogle Scholar
  41. 41.
    Essandoh K, Fan G-C (2014) Role of extracellular and intracellular microRNAs in sepsis. Biochim Biophys Acta 1842(11):2155–2162PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Barry OP, Praticò D, Savani RC, FitzGerald GA (1998) Modulation of monocyte-endothelial cell interactions by platelet microparticles. J Clin Investig 102(1):136–144PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Weber A-A, Köppen HO, Schrör K (2000) Platelet-derived microparticles stimulate coronary artery smooth muscle cell mitogenesis by a PDGF-independent mechanism. Thromb Res 98(5):461–466PubMedCrossRefGoogle Scholar
  44. 44.
    Nieuwland R, Berckmans RJ, McGregor S, Böing AN, Romijn FP, Westendorp RG, Hack CE, Sturk A (2000) Cellular origin and procoagulant properties of microparticles in meningococcal sepsis. Blood J 95(3):930–935Google Scholar
  45. 45.
    Ogura H, Kawasaki T, Tanaka H, Koh T, Tanaka R, Ozeki Y, Hosotsubo H, Kuwagata Y, Shimazu T, Sugimoto H (2001) Activated platelets enhance microparticle formation and platelet-leukocyte interaction in severe trauma and sepsis. J Trauma Acute Care Surg 50(5):801–809CrossRefGoogle Scholar
  46. 46.
    Irani K (2000) Oxidant signaling in vascular cell growth, death, and survival. Circ Res 87:179–183PubMedCrossRefGoogle Scholar
  47. 47.
    Finazzi-Agrò A, Menichelli A, Persiani M, Biancini G, Del Principe D (1982) Hydrogen peroxide release from human blood platelets. Biochim Biophys Acta Gen Subj 718(1):21–25CrossRefGoogle Scholar
  48. 48.
    Leoncini G, Maresca M, Colao C (1991) Oxidative metabolism of human platelets. Biochem Int 25(4):647–655PubMedGoogle Scholar
  49. 49.
    Marcus AJ, Silk ST, Safier LB, Ullman HL (1977) Superoxide production and reducing activity in human platelets. J Clin Invest 59:149–158PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Janiszewski M, Do Carmo AO, Ma P, Silva E, Knobel E, Laurindo FRM (2004) Platelet-derived exosomes of septic individuals possess proapoptotic NAD(P)H oxidase activity: a novel vascular redox pathway. Crit Care Med 32(3):818–825PubMedCrossRefGoogle Scholar
  51. 51.
    Caccese D, Praticò D, Ghiselli A, Natoli S, Pignatelli P, Sanguigni V, Iuliano L, Violi F (2000) Superoxide anion and hydroxyl radical release by collagen-induced platelet aggregation—role of arachidonic acid metabolism. Thromb Haemost 83(3):485–490PubMedGoogle Scholar
  52. 52.
    Azevedo LCP, Janiszewski M, Pontieri V, Pedro MA, Bassi E, Tucci PJF, Laurindo FRM (2007) Platelet-derived exosomes from septic shock patients induce myocardial dysfunction. Crit Care 11(6):R120–R120PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Kumar A, Haery C, Parrillo JE (2001) Myocardial dysfunction in septic shock: part I. Clinical manifestation of cardiovascular dysfunction. J Cardiothorac Vasc Anesth 15(3):364–376PubMedCrossRefGoogle Scholar
  54. 54.
    Paulus WJ, Bronzwaer JGF (2002) Myocardial contractile effects of nitric oxide. Heart Fail Rev 7(4):371–383PubMedCrossRefGoogle Scholar
  55. 55.
    Ullrich R, Scherrer-Crosbie M, Bloch KD, Ichinose F, Nakajima H, Picard MH, Zapol WM, Quezado ZM (2000) Congenital deficiency of nitric oxide synthase 2 protects against endotoxin-induced myocardial dysfunction in mice. Circulation 102(12):1440–1446PubMedCrossRefGoogle Scholar
  56. 56.
    Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R (2000) Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res 87(3):241–247PubMedCrossRefGoogle Scholar
  57. 57.
    Gambim MH, do Carmo Ade O, Marti L, Verissimo-Filho S, Lopes LR, Janiszewski M (2007) Platelet-derived exosomes induce endothelial cell apoptosis through peroxynitrite generation: experimental evidence for a novel mechanism of septic vascular dysfunction. Crit Care 11(5):R107–R107PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Zhu C, Wang X, Qiu L, Peeters-Scholte C, Hagberg H, Blomgren K (2004) Nitrosylation precedes caspase-3 activation and translocation of apoptosis-inducing factor in neonatal rat cerebral hypoxia-ischaemia. J Neurochem 90(2):462–471PubMedCrossRefGoogle Scholar
  59. 59.
    Albina JE, Cui S, Mateo RB, Reichner JS (1993) Nitric oxide-mediated apoptosis in murine peritoneal macrophages. J Immunol 150(11):5080–5085PubMedGoogle Scholar
  60. 60.
    Rössig L, Fichtlscherer B, Breitschopf K, Haendeler J, Zeiher AM, Mülsch A, Dimmeler S (1999) Nitric oxide inhibits caspase-3 by S-nitrosation in vivo. J Biol Chem 274(11):6823–6826PubMedCrossRefGoogle Scholar
  61. 61.
    Humphreys DT, Westman BJ, Martin DIK, Preiss T (2005) MicroRNAs control translation initiation by inhibiting eukaryotic initiation factor 4E/cap and poly(A) tail function. Proc Natl Acad Sci U S A 102(47):16961–16966PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Fabian MR, Sonenberg N (2012) The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC. Nat Struct Mol Biol 19(6):586–593PubMedCrossRefGoogle Scholar
  63. 63.
    Jackson RJ, Standart N (2007) How do microRNAs regulate gene expression? Sci STKE 367(367):re1Google Scholar
  64. 64.
    Sayed D, Abdellatif M (2011) MicroRNAs in development and disease. Physiol Rev 91(3):827–887PubMedCrossRefGoogle Scholar
  65. 65.
    Zhu H, Fan G-C (2011) Extracellular/circulating microRNAs and their potential role in cardiovascular disease. Am J Cardiovasc Dis 1(2):138–149PubMedPubMedCentralGoogle Scholar
  66. 66.
    Zhu H, Fan G-C (2012) Role of microRNAs in the reperfused myocardium towards post-infarct remodelling. Cardiovasc Res 94(2):284–292PubMedCrossRefGoogle Scholar
  67. 67.
    Wang H, Zhang P, Chen W, Feng D, Jia Y, Xie L (2012) Serum microRNA signatures identified by Solexa sequencing predict sepsis patients’ mortality: a prospective observational study. PLoS One 7(6):e38885PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Benz F, Roy S, Trautwein C, Roderburg C, Luedde T (2016) Circulating microRNAs as biomarkers for sepsis. Int J Mol Sci 17(78):1–17Google Scholar
  69. 69.
    Taïbi F, Meuth VM-l, Massy ZA, Metzinger L (2014) miR-223 : an inflammatory oncomiR enters the cardiovascular field. Biochim Biophys Acta 1842:1001–1009PubMedCrossRefGoogle Scholar
  70. 70.
    Wang X, Huang W, Yang Y, Wang Y, Peng T, Chang J, Caldwell CC, Zingarelli B, Fan GC (2014) Loss of duplexmiR-223 (5p and 3p) aggravates myocardial depression and mortality in polymicrobial sepsis. Biochim Biophys Acta Mol Basis Dis 1842(5):701–711CrossRefGoogle Scholar
  71. 71.
    Akira S, Nishio Y, Inoue M, Wang X-J, We S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77(1):63–71PubMedCrossRefGoogle Scholar
  72. 72.
    Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282(13):9358–9363PubMedCrossRefGoogle Scholar
  73. 73.
    Ieda M, Kanazawa H, Kimura K, Hattori F, Ieda Y, Taniguchi M, Lee J-K, Matsumura K, Tomita Y, Miyoshi S, Shimoda K, Makino S, Sano M, Kodama I, Ogawa S, Fukuda K (2007) Sema3a maintains normal heart rhythm through sympathetic innervation patterning. Nat Med 13(5):604–612PubMedCrossRefGoogle Scholar
  74. 74.
    Tabet F, Vickers KC, Cuesta Torres LF, Wiese CB, Shoucri BM, Lambert G, Catherinet C, Prado-Lourenco L, Levin MG, Thacker S, Sethupathy P, Barter PJ, Remaley AT, Rye K-A (2014) HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells. Nat Commun 5:3292–3292PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Wang X, Gu H, Qin D, Yang L, Huang W, Essandoh K, Wang Y, Caldwell CC, Peng T, Zingarelli B, Fan G-C (2015) Exosomal miR-223 contributes to mesenchymal stem cell-elicited cardioprotection in polymicrobial sepsis. Sci Rep 5:1–16Google Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  • Valter Vinícius Silva Monteiro
    • 1
  • Jordano Ferreira Reis
    • 1
  • Rafaelli de Souza Gomes
    • 2
  • Kely Campos Navegantes
    • 2
  • Marta Chagas Monteiro
    • 2
    Email author
  1. 1.School of Pharmacy, Health Science Institute, Federal University of Pará/UFPABelémBrazil
  2. 2.Pharmaceutical Science Post-Graduation Program, Health Science Institute, Federal University of Pará/UFPABelémBrazil

Personalised recommendations