Skip to main content

Advertisement

SpringerLink
Log in

Anti-inflammatory effect of oxytocin in rat myocardial infarction

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

While an increasing amount of evidence demonstrates the homeostatic functions of the cardiac oxytocin (OT) system, less is known about the role of this hormone in the injured heart. The current study examined the effect of OT infusion on cell apoptosis, expression of proliferating cell nuclear antigen (PCNA) and inflammation in the acute and subacute phases of myocardial infarction (MI). Prior MI male Sprague-Dawley rats were infused subcutaneously with OT 25 or 125 ng/(kg h) for 3 or 7 days. Saline-treated MI and sham-operated rats served as controls. Echocardiography and analysis of cardiac sections were used to disclose OT actions. Left ventricular fractional shortening, estimated to be 46.0 ± 1.8% in sham controls, declined to 21.1 ± 3.3% in vehicle-treated MI rats and was improved to 34.2 ± 2.1 and to 30.9 ± 2.5% after treatment with OT 25 and 125 ng/(kg h), respectively. OT infusion resulted in: (1) increase of cells expressing PCNA in the infarct zone, diminished cell apoptosis and fibrotic deposits in the remote myocardium; (2) suppression of inflammation by reduction of neutrophils, macrophages and T lymphocytes; (3) depression of the expression of proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 with promotion of transforming growth factor-beta. OT treatment reduced expression of atrial and brain natriuretic peptides in the infarcted ventricle, as well as the concentration of both peptides in the circulation. These results indicate that continuous OT delivery reduces inflammation and apoptosis in infarcted and remote myocardium, thus improving function in the injured heart.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Abbate A, Bonanno E, Mauriello A, Bussani R, Biondi-Zoccai GG, Liuzzo G, Silvestri F, Dobrina A, Baldi F, Pandolfi F, Biasucci LM, Baldi A, Spagnoli LG, Crea F (2004) Widespread myocardial inflammation and infarct-related artery patency. Circulation 110:46–50

    Article  PubMed  Google Scholar 

  2. Abdel-Latif A, Zuba-Surma EK, Case J, Tiwari S, Hunt G, Ranjan S, Vincent RJ, Srour EF, Bolli R, Dawn B (2008) TGF-beta1 enhances cardiomyogenic differentiation of skeletal muscle-derived adult primitive cells. Basic Res Cardiol 103:514–524

    Article  CAS  PubMed  Google Scholar 

  3. Belosjorow S, Bolle I, Duschin A, Heusch G, Schulz R (2003) TNF-alpha antibodies are as effective as ischemic preconditioning in reducing infarct size in rabbits. Am J Physiol Heart Circ Physiol 284:H927–H930

    CAS  PubMed  Google Scholar 

  4. Biyikli NK, Tugtepe H, Sener G, Velioglu-Ogunc A, Cetinel S, Midillioglu S (2006) Oxytocin alleviates oxidative renal injury in pyelonephritic rats via a neutrophil-dependent mechanism. Peptides 27:2249–2257

    Article  CAS  PubMed  Google Scholar 

  5. Bodi V, Sanchis J, Nunez J, Mainar L, Minana G, Benet I, Solano C, Chorro FJ, Llacer A (2008) Uncontrolled immune response in acute myocardial infarction: unraveling the thread. Am J Heart 156:1065–1073

    Article  CAS  Google Scholar 

  6. Cattaneo MG, Lucci G, Vicentini LM (2009) Oxytocin stimulates in vitro angiogenesis via a Pyk-2/Src-dependent mechanism. Exp Cell Res 315:3210–3219

    Article  PubMed  Google Scholar 

  7. Chan AY, Soltys CL, Young ME, Proud CG, Dyck JR (2004) Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte. J Biol Chem 279:32771–32779

    Article  CAS  PubMed  Google Scholar 

  8. Chaouat G (2007) The Th1/Th2 paradigm: still important in pregnancy? Semin Immunopathol 29:95–113

    Article  PubMed  Google Scholar 

  9. Chorianopoulos E, Heger T, Lutz M, Frank D, Bea F, Katus HA, Frey N (2009) FGF-inducible 14-kDa protein (Fn14) is regulated via the RhoA/ROCK kinase pathway in cardiomyocytes and mediates nuclear factor-kappaB activation by TWEAK. Basic Res Cardiol [Epub ahead of print]. doi:10.1007/s00395-009-0046-y

  10. Danalache BA, Paquin J, Donghao W, Grygorczyk R, Moore JC, Gutkowska J, Jankowski M (2007) Nitric oxide signaling in oxytocin-mediated cardiomyogenesis. Stem Cells 25:679–688

    Article  CAS  PubMed  Google Scholar 

  11. Devost D, Carrier ME, Zingg HH (2008) Oxytocin-induced activation of eukaryotic elongation factor 2 in myometrial cells is mediated by protein kinase C. Endocrinology 149:131–138

    Article  CAS  PubMed  Google Scholar 

  12. Dörge H, Schulz R, Belosjorow S, Post H, van de Sand A, Konietzka I, Frede S, Hartung T, Vinten-Johansen J, Youker KA, Entman ML, Erbel R, Heusch G (2002) Coronary microembolization: the role of TNF-α in contractile dysfunction. J Mol Cell Cardiol 34:51–62

    Article  PubMed  Google Scholar 

  13. Ebermann L, Piper C, Kühl U, Klingel K, Schlattner U, Siafarikas N, Zeichhardt H, Schultheiss HP, Dörner A (2009) Impact of myocardial inflammation on cytosolic and mitochondrial creatine kinase activity and expression. Basic Res Cardiol 104:247–257

    Article  CAS  PubMed  Google Scholar 

  14. Elands J, Resink A, de Kloet ER (1990) Neurohypophyseal hormone receptors in the rat thymus, spleen, and lymphocytes. Endocrinology 126:2703–2710

    Article  CAS  PubMed  Google Scholar 

  15. Florian M, Jankowski M, Gutkowska J (2010) Oxytocin regulates glucose uptake in neonatal rat cardiomyocytes. Endocrinology. doi:10.1210/en.2009-0624

  16. Frangogiannis NG (2008) The immune system and cardiac repair. Pharmacol Res 58:88–111

    Article  CAS  PubMed  Google Scholar 

  17. Frangogiannis NG, Lindsey ML, Michael LH, Youker KA, Bressler RB, Mendoza LH, Smith CW, Entman ML (1998) Resident cardiac mast cells degranulate and release preformed TNF-alpha, initiating the cytokine cascade in experimental canine myocardial ischemia/reperfusion. Circulation 98:699–710

    CAS  PubMed  Google Scholar 

  18. Frantz S, Hu K, Adamek A, Wolf J, Sallam A, Maier SK, Lonning S, Ling H, Ertl G, Bauersachs J (2008) Transforming growth factor beta inhibition increases mortality and left ventricular dilatation after myocardial infarction. Basic Res Cardiol 103:485–492

    Article  CAS  PubMed  Google Scholar 

  19. Gassanov N, Devost D, Danalache B, Noiseux N, Jankowski M, Zingg HH, Gutkowska J (2008) Functional activity of the carboxyl-terminally extended oxytocin precursor peptide during cardiac differentiation of embryonic stem cells. Stem Cells 26:45–54

    Article  PubMed  Google Scholar 

  20. Graham LN, Smith PA, Huggett RJ, Stoker JB, Mackintosh AF, Mary D (2004) Sympathetic drive in anterior and inferior uncomplicated acute myocardial infarction. Circulation 109:2285–2289

    Article  PubMed  Google Scholar 

  21. Gutkowska J, Jankowski M (2008) Oxytocin revisited: it is also a cardiovascular hormone. J Am Soc Hypertens 2:318–325

    Article  Google Scholar 

  22. Gutkowska J, Jankowski M, Lambert C, Mukaddam-Daher S, Zingg HH, McCann SM (1997) Oxytocin releases atrial natriuretic peptide by combining with oxytocin receptors in the heart. Proc Natl Acad Sci USA 94:11704–11709

    Article  CAS  PubMed  Google Scholar 

  23. Haanwinckel MA, Elias LK, Favaretto AL, Gutkowska J, McCann SM, Antunes-Rodrigues J (1995) Oxytocin mediates atrial natriuretic peptide release and natriuresis after volume expansion in the rat. Proc Natl Acad Sci USA 92:7902–7906

    Article  CAS  PubMed  Google Scholar 

  24. Hausenloy DJ, Yellon DM (2004) New directions for protecting the heart against ischaemia-reperfusion injury: targeting the reperfusion injury salvage kinase (RISK)-pathway. Cardiovasc Res 61:448–460

    Article  CAS  PubMed  Google Scholar 

  25. Heusch G (2009) No RISK, no … cardioprotection? A critical perspective. Cardiovasc Res 84:173–175

    Article  CAS  PubMed  Google Scholar 

  26. Horman S, Beauloye C, Vertommen D, Vanoverschelde JL, Hue L, Rider MH (2003) Myocardial ischemia and increased heart work modulate the phosphorylation state of eukaryotic elongation factor-2. J Biol Chem 278:41970–41976

    Article  CAS  PubMed  Google Scholar 

  27. Hoshinaga K, Mohanakumar T, Goldman MH, Wolfgang TC, Szentpetery S, Lee HM, Lower RR (1984) Clinical significance of in situ detection of T lymphocyte subsets and monocyte/macrophage lineages in heart allografts. Transplantation 38:634–637

    Article  CAS  PubMed  Google Scholar 

  28. Indrambarya T, Boyd JH, Wang Y, McConechy M, Walley KR (2009) Low-dose vasopressin infusion results in increased mortality and cardiac dysfunction following ischemia-reperfusion injury in mice. Crit Care 13:R98

    Article  PubMed  Google Scholar 

  29. Iseri SO, Sener G, Saglam B, Gedik N, Ercan F, Yegen BC (2005) Oxytocin ameliorates oxidative colonic inflammation by a neutrophil-dependent mechanism. Peptides 26:483–491

    Article  CAS  PubMed  Google Scholar 

  30. Jankowski M, Danalache B, Wang D, Bhat P, Hajjar F, Marcinkiewicz M, Paquin J, McCann SM, Gutkowska J (2004) Oxytocin in cardiac ontogeny. Proc Natl Acad Sci USA 101:13074–13079

    Article  CAS  PubMed  Google Scholar 

  31. Jankowski M, Hajjar F, Kawas SA, Mukaddam-Daher S, Hoffman G, McCann SM, Gutkowska J (1998) Rat heart: a site of oxytocin production and action. Proc Natl Acad Sci USA 95:14558–14563

    Article  CAS  PubMed  Google Scholar 

  32. Jankowski M, Wang D, Hajjar F, Mukaddam-Daher S, McCann SM, Gutkowska J (2000) Oxytocin and its receptors are synthesized in the rat vasculature. Proc Natl Acad Sci USA 97:6207–6211

    Article  CAS  PubMed  Google Scholar 

  33. Jardine DL, Charles CJ, Ashton RK, Bennett SI, Whitehead M, Frampton CM, Nicholls MG (2005) Increased cardiac sympathetic nerve activity following acute myocardial infarction in a sheep model. J Physiol 565:325–333

    Article  CAS  PubMed  Google Scholar 

  34. Kewalramani G, Puthanveetil P, Wang F, Kim MS, Deppe S, Abrahani A, Luciani DS, Johnson JD, Rodrigues B (2009) AMP-activated protein kinase confers protection against TNF-α-induced cardiac cell death. Cardiovasc Res 84:42–53

    Article  CAS  PubMed  Google Scholar 

  35. Kobayashi H, Yasuda S, Bao N, Iwasa M, Kawamura I, Yamada Y, Yamaki T, Sumi S, Ushikoshi H, Nishigaki K, Takemura G, Fujiwara T, Fujiwara H, Minatoguchi S (2009) Post-infarct treatment with oxytocin improves function and remodeling via activating cell survival signals and angiogenesis. J Cardiovascul Pharmacol [Epub ahead of print]. doi:10.1097/FJC.0b013e3181bfac02

  36. Lee ES, Uhm KO, Lee YM, Kwon J, Park SH, Soo KH (2008) Oxytocin stimulates glucose uptake in skeletal muscle cells through the calcium-CaMKK-AMPK pathway. Regul Pept 151:71–74

    Article  CAS  PubMed  Google Scholar 

  37. Marsin AS, Bouzin C, Bertrand L, Hue L (2002) The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. J Biol Chem 277:30778–30783

    Article  CAS  PubMed  Google Scholar 

  38. McCann SM, Antunes-Rodrigues J, Jankowski M, Gutkowska J (2002) Oxytocin, vasopressin and atrial natriuretic peptide control body fluid homeostasis by action on their receptors in brain, cardiovascular system and kidney. Prog Brain Res 139:309–328

    Article  CAS  PubMed  Google Scholar 

  39. Miki T, Miura T, Tanno M, Nishihara M, Naitoh K, Sato T, Takahashi A, Shimamoto K (2007) Impairment of cardioprotective PI3K-AKT signaling by post-infarct ventricular remodeling is compensated by an ERK-mediated pathway. Basic Res Cardiol 102:163–170

    Article  CAS  PubMed  Google Scholar 

  40. Miura T, Miki T (2008) Limitation of myocardial infarct size in the clinical setting: current status and challenges in translating animal experiments into clinical therapy. Basic Res Cardiol 103:501–513

    Article  PubMed  Google Scholar 

  41. Mukaddam-Daher S, Lin YL, Gutkowska J, Cardinal R (2001) Negative inotropic and chronotropic effects of oxytocin. Hypertension 38:292–296

    CAS  PubMed  Google Scholar 

  42. Nagoshi T, Matsui T, Aoyama T, Leri A, Anversa P, Li L, Ogawa W, del Monte F, Gwathmey JK, Grazette L, Hemmings BA, Kass DA, Champion HC, Rosenzweig A (2005) PI3K rescues the detrimental effects of chronic Akt activation in the heart during ischemia/reperfusion injury. J Clin Invest 115:2128–2138

    Article  CAS  PubMed  Google Scholar 

  43. Ndiaye K, Poole DH, Pate JL (2008) Expression and regulation of functional oxytocin receptors in bovine T lymphocytes. Biol Reprod 78:786–793

    Article  CAS  PubMed  Google Scholar 

  44. Nian M, Lee P, Khaper N, Liu P (2004) Inflammatory cytokines and postmyocardial infarction remodeling. Circ Res 94:1543–1553

    Article  CAS  PubMed  Google Scholar 

  45. Ondrejcakova M, Ravingerova T, Bakos J, Pancza D, Jezova D (2009) Oxytocin exerts protective effects on in vitro myocardial injury induced by ischemia and reperfusion. Can J Physiol Pharmacol 87:137–142

    Article  CAS  PubMed  Google Scholar 

  46. Palojoki E, Saraste A, Eriksson A, Pulkki K, Kallajoki M, Voipio-Pulkki L-M, Tikkanen I (2001) Cardiomyocyte apoptosis and ventricular remodeling after myocardial infarction in rats. Am J Physiol Heart Circ Physiol 280:H2726–H2731

    CAS  PubMed  Google Scholar 

  47. Pantos C, Mourouzis I, Markakis K, Tsagoulis N, Panagiotou M, Cokkinos DV (2008) Long-term thyroid hormone administration reshapes left ventricular chamber and improves cardiac function after myocardial infarction in rats. Basic Res Cardiol 103:308–318

    Article  CAS  PubMed  Google Scholar 

  48. Paquin J, Danalache BA, Jankowski M, McCann SM, Gutkowska J (2002) Oxytocin induces differentiation of P19 embryonic stem cells to cardiomyocytes. Proc Natl Acad Sci USA 99:9550–9555

    Article  CAS  PubMed  Google Scholar 

  49. Petersson M, Lundeberg T, Sohlstrom A, Wiberg U, Uvnas-Moberg K (1998) Oxytocin increases the survival of musculocutaneous flaps. Naunyn Schmiedebergs Arch Pharmacol 357:701–704

    Article  CAS  PubMed  Google Scholar 

  50. Petersson M, Wiberg U, Lundeberg T, Uvnas-Moberg K (2001) Oxytocin decreases carrageenan induced inflammation in rats. Peptides 22:1479–1484

    Article  CAS  PubMed  Google Scholar 

  51. Russell RR 3rd, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M, Giordano FJ, Mu J, Birnbaum MJ, Young LH (2004) AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 114:495–503

    CAS  PubMed  Google Scholar 

  52. Schmid B, Wong S, Mitchell BF (2001) Transcriptional regulation of oxytocin receptor by interleukin-1beta and interleukin-6. Endocrinology 142:1380–1385

    Article  CAS  PubMed  Google Scholar 

  53. Schuh A, Liehn EA, Sasse A, Schneider R, Neuss S, Weber C, Kelm M, Merx MW (2009) Improved left ventricular function after transplantation of microspheres and fibroblasts in a rat model of myocardial infarction. Basic Res Cardiol 104:403–411

    Article  PubMed  Google Scholar 

  54. Schulz R, Aker S, Belosjorow S, Heusch G (2004) TNFalpha in ischemia/reperfusion injury and heart failure. Basic Res Cardiol 99:8–11

    Article  CAS  PubMed  Google Scholar 

  55. Skyschally A, Gres P, Hoffmann S, Haude M, Erbel R, Schulz R, Heusch G (2007) Bidirectional role of tumor necrosis factor-alpha in coronary microembolization: progressive contractile dysfunction versus delayed protection against infarction. Circ Res 100:140–146

    Article  CAS  PubMed  Google Scholar 

  56. Spangelo BL, de Holl PD, Kalabay L, Bond BR, Arnaud P (1994) Neurointermediate pituitary lobe cells synthesize and release interleukin-6 in vitro: effects of lipopolysaccharide and interleukin-1 beta. Endocrinology 135:556–563

    Article  CAS  PubMed  Google Scholar 

  57. Szeto A, Nation DA, Mendez AJ, Dominguez-Bendala J, Brooks LG, Schneiderman N, McCabe PM (2008) Oxytocin attenuates NADPH-dependent superoxide activity and IL-6 secretion in macrophages and vascular cells. Am J Physiol Endocrinol Metab 295:E1495–E1501

    Article  CAS  PubMed  Google Scholar 

  58. Tabata C, Ogita K, Sato K, Nakamura H, Qing Z, Negoro H, Kumasawa K, Temma-Asano K, Tsutsui T, Nishimori K, Kimura T (2009) Calcineurin/NFAT pathway: a novel regulator of parturition. Am J Reprod Immunol 62:44–50

    Article  CAS  PubMed  Google Scholar 

  59. Tiede K, Melchior-Becker A, Fischer JW (2009) Transcriptional and posttranscriptional regulators of biglycan in cardiac fibroblasts. Basic Res Cardiol. doi:10.1007/s00395-009-0049-8

  60. Wernli G, Hasan W, Bhattacherjee A, van Rooijen N, Smith PG (2009) Macrophage depletion suppresses sympathetic hyperinnervation following myocardial infarction. Basic Res Cardiol 104:681–693

    Article  PubMed  Google Scholar 

  61. Yang XM, Philipp S, Downey JM, Cohen MV (2006) Atrial natriuretic peptide administered just prior to reperfusion limits infarction in rabbit hearts. Basic Res Cardiol 101:311–318

    Article  CAS  PubMed  Google Scholar 

  62. Ytrehus K, Liu Y, Tsuchida A (1994) Rat and rabbit heart infarction: effects of anesthesia, perfusate, risk zone, and method of infarct sizing. Am J Physiol 267:H2383–H2390

    CAS  PubMed  Google Scholar 

  63. Zimmermann O, Bienek-Ziolkowski M, Wolf B, Vetter M, Baur R, Mailänder V, Hombach V, Torzewski J (2009) Myocardial inflammation and non-ischaemic heart failure: is there a role for C-reactive protein? Basic Res Cardiol 104:591–599

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We appreciate the editorial assistance of Ovid da Silva (Research Support Office, CHUM, Hôtel-Dieu Research Center) as well as the secretarial help of Jennifer Lelievre. This work was supported by the Canadian Institutes of Health Research (MOP-53217 to J. G., G. B. and M. J.); and the Canadian Heart and Stroke Foundation (NET SRD-63193 to J. G., G. B. and M. J.).

Author information

Authors and Affiliations

  1. Centre de Recherche, Centre Hospitalier de l’Université de Montréal (CRCHUM), Hôtel-Dieu, Pavillon Jeanne-Mance 3840, rue Saint-Urbain, Montreal, QC, H2W 1T8, Canada

    Marek Jankowski, Vickram Bissonauth, Lan Gao, Marius Gangal, Donghao Wang, Bogdan Danalache, Yang Wang, Ekatherina Stoyanova, Guy Cloutier, Gilbert Blaise & Jolanta Gutkowska

Authors
  1. Marek Jankowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vickram Bissonauth
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lan Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marius Gangal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Donghao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bogdan Danalache
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ekatherina Stoyanova
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Guy Cloutier
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gilbert Blaise
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jolanta Gutkowska
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marek Jankowski.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jankowski, M., Bissonauth, V., Gao, L. et al. Anti-inflammatory effect of oxytocin in rat myocardial infarction. Basic Res Cardiol 105, 205–218 (2010). https://doi.org/10.1007/s00395-009-0076-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-009-0076-5

Keywords

Search

Navigation