Download PDF
Thromb Haemost 2014; 112(06): 1110-1119
DOI: 10.1160/th14-08-0703
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

RNase1 prevents the damaging interplay between extracellular RNA and tumour necrosis factor-α in cardiac ischaemia/reperfusion injury

Hector A. Cabrera-Fuentes
1   Institute of Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany
5   Kazan Federal University, Department of Microbiology, Kazan, Russia
,
Marisol Ruiz-Meana   *
6   Hospital Universitari Vall d´Hebron, Laboratorio de Cardiología Experimental, Barcelona, Spain
,
Sakine Simsekyilmaz   *
7   Institute of Molecular Cardiovascular Research, RWTH, Aachen, Germany
,
Sawa Kostin   *
8   Core Lab for Molecular and Structural Biology, Max-Planck-Institute, Bad Nauheim, Germany
,
Javier Inserte
6   Hospital Universitari Vall d´Hebron, Laboratorio de Cardiología Experimental, Barcelona, Spain
,
Mona Saffarzadeh
1   Institute of Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany
,
Sebastian P. Galuska
1   Institute of Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany
,
Vijith Vijayan
3   Institute of Anatomy and Cell Biology II, Medical School, Justus-Liebig-University, Giessen, Germany
,
Ignasi Barba
6   Hospital Universitari Vall d´Hebron, Laboratorio de Cardiología Experimental, Barcelona, Spain
,
Guillermo Barreto
9   LOEWE Research Group Lung Cancer Epigenetics, Max-Planck-Institute, Bad Nauheim, Germany
,
Silvia Fischer
1   Institute of Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany
,
Günter Lochnit
1   Institute of Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany
,
Olga N. Ilinskaya
5   Kazan Federal University, Department of Microbiology, Kazan, Russia
,
Eveline Baumgart-Vogt
3   Institute of Anatomy and Cell Biology II, Medical School, Justus-Liebig-University, Giessen, Germany
,
Andreas Böning
4   Department of Cardiovascular Surgery, Medical School, Justus-Liebig-University, Giessen, Germany
,
Sandrine Lecour
10   Hatter Institute for Cardiovascular Research, University of Cape Town, Cape Town, South Africa
,
Derek J. Hausenloy
11   The Hatter Cardiovascular Institute, University College London, London, UK
,
Elisa A. Liehn
7   Institute of Molecular Cardiovascular Research, RWTH, Aachen, Germany
,
David Garcia-Dorado
6   Hospital Universitari Vall d´Hebron, Laboratorio de Cardiología Experimental, Barcelona, Spain
,
Klaus-Dieter Schlüter
2   Institute of Physiology, Medical School, Justus-Liebig-University, Giessen, Germany
,
Klaus T. Preissner
1   Institute of Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany
5   Kazan Federal University, Department of Microbiology, Kazan, Russia
› Author Affiliations
Further Information

Publication History

Received: 26 August 2014

Accepted after minor revision: 20 September 2014

Publication Date:
29 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Despite optimal therapy, the morbidity and mortality of patients presenting with an acute myocardial infarction (MI) remain significant, and the initial mechanistic trigger of myocardial “ischaemia/reperfusion (I/R) injury” remains greatly unexplained. Here we show that factors released from the damaged cardiac tissue itself, in particular extracellular RNA (eRNA) and tumour-necrosis-factor α (TNF-α), may dictate I/R injury. In an experimental in vivo mouse model of myocardial I/R as well as in the isolated I/R Langendorff-perfused rat heart, cardiomyocyte death was induced by eRNA and TNF-α. Moreover, TNF-α promoted further eRNA release especially under hypoxia, feeding a vicious cell damaging cycle during I/R with the massive production of oxygen radicals, mitochondrial obstruction, decrease in antioxidant enzymes and decline of cardiomyocyte functions. The administration of RNase1 significantly decreased myocardial infarction in both experimental models. This regimen allowed the reduction in cytokine release, normalisation of antioxidant enzymes as well as preservation of cardiac tissue. Thus, RNase1 administration provides a novel therapeutic regimen to interfere with the adverse eRNA-TNF-α interplay and significantly reduces or prevents the pathological outcome of ischaemic heart disease.

Keywords

Inflammatory mediators - ischaemic heart disease - cytokines - cardiology

* Equal contributions.


 

  • References

  • 1 Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med 2007; 357: 1121-1135.
    CrossrefPubMedSearch in Google Scholar
  • 2 Hausenloy DJ, Yellon DM. Myocardial ischaemia-reperfusion injury: a neglected therapeutic target. J Clin Invest 2013; 123: 92-100.
    CrossrefPubMedSearch in Google Scholar
  • 3 Piper HM, Garcia-Dorado D, Ovize M. A fresh look at reperfusion injury. Cardiovasc Res 1998; 38: 291-300.
    CrossrefPubMedSearch in Google Scholar
  • 4 Ruiz-Meana M, Abellan A, Miro-Casas E. et al. Opening of mitochondrial permeability transition pore induces hypercontracture in Ca2+ overloaded cardiac myocytes. Basic Res Cardiol 2007; 102: 542-552.
    CrossrefPubMedSearch in Google Scholar
  • 5 Di Lisa F, Carpi A, Giorgio V. et al. The mitochondrial permeability transition pore and cyclophilin D in cardioprotection. Biochim Biophys Acta 2011; 1813: 1316-1322.
    CrossrefPubMedSearch in Google Scholar
  • 6 Di Lisa F, Kaludercic N, Carpi A. et al. Mitochondria and vascular pathology. Pharmacol Rep 2009; 61: 123-130.
    CrossrefPubMedSearch in Google Scholar
  • 7 Abdallah Y, Wolf C, Meuter K. et al. Preconditioning with diazoxide prevents reoxygenation-induced rigor-type hypercontracture. J Mol Cell Cardiol 2010; 48: 270-276.
    CrossrefPubMedSearch in Google Scholar
  • 8 Ladilov Y, Efe O, Schafer C. et al. Reoxygenation-induced rigor-type contracture. J Mol Cell Cardiol 2003; 35: 1481-1490.
    CrossrefPubMedSearch in Google Scholar
  • 9 Garcia-Dorado D, Ruiz-Meana M, Inserte J. et al. Calcium-mediated cell death during myocardial reperfusion. Cardiovasc Res 2012; 94: 168-180.
    CrossrefPubMedSearch in Google Scholar
  • 10 Zhao Q, Shao L, Hu X. et al. Lipoxin a4 preconditioning and postconditioning protect myocardial ischaemia/reperfusion injury in rats. Mediators Inflam 2013; 2013: 231351.
    PubMedSearch in Google Scholar
  • 11 Schafer C, Ladilov Y, Inserte J. et al. Role of the reverse mode of the Na+/Ca2+ exchanger in reoxygenation-induced cardiomyocyte injury. Cardiovasc Res 2001; 51: 241-250.
    CrossrefPubMedSearch in Google Scholar
  • 12 Ruiz-Meana M, Garcia-Dorado D, Julia M. et al. Protective effect of HOE642, a selective blocker of Na+-H+ exchange, against the development of rigor contracture in rat ventricular myocytes. Exp Physiol 2000; 85: 17-25.
    PubMedSearch in Google Scholar
  • 13 Agullo L, Garcia-Dorado D, Escalona N. et al. Membrane association of nitric oxide-sensitive guanylyl cyclase in cardiomyocytes. Cardiovasc Res 2005; 68: 65-74.
    CrossrefPubMedSearch in Google Scholar
  • 14 Hausenloy DJ, Mwamure PK, Venugopal V. et al. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet 2007; 370: 575-579.
    CrossrefPubMedSearch in Google Scholar
  • 15 Thielmann M, Kottenberg E, Kleinbongard P. et al. Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial. Lancet 2013; 382: 597-604.
    CrossrefPubMedSearch in Google Scholar
  • 16 Botker HE, Kharbanda R, Schmidt MR. et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 2010; 375: 727-734.
    CrossrefPubMedSearch in Google Scholar
  • 17 Heusch G. Cardioprotection: chances and challenges of its translation to the clinic. Lancet 2013; 381: 166-175.
    CrossrefPubMedSearch in Google Scholar
  • 18 Ovize M, Thibault H, Przyklenk K. Myocardial conditioning: opportunities for clinical translation. Circ Res 2013; 113: 439-450.
    CrossrefPubMedSearch in Google Scholar
  • 19 Santos ES, Baltar VT, Pereira MP. et al. Comparison between cardiac troponin I and CK-MB mass in acute coronary syndrome without st elevation. Arqu Bras Cardiol 2011; 96: 179-187.
    PubMedSearch in Google Scholar
  • 20 McErlean ES, Deluca SA, van Lente F. et al. Comparison of troponin T versus creatine kinase-MB in suspected acute coronary syndromes. Am J Cardiol 2000; 85: 421-426.
    CrossrefPubMedSearch in Google Scholar
  • 21 Kannemeier C, Shibamiya A, Nakazawa F. et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci USA 2007; 104: 6388-6393.
    CrossrefPubMedSearch in Google Scholar
  • 22 Deindl E, Fischer S, Preissner KT. New directions in inflammation and immunity: the multi-functional role of the extracellular RNA/RNase system. Indian J Biochem Biophys 2009; 46: 461-466.
    PubMedSearch in Google Scholar
  • 23 Fischer S, Gerriets T, Wessels C. et al. Extracellular RNA mediates endothelial-cell permeability via vascular endothelial growth factor. Blood 2007; 110: 2457-2465.
    CrossrefPubMedSearch in Google Scholar
  • 24 Fischer S, Grantzow T, Pagel JI. et al. Extracellular RNA promotes leukocyte recruitment in the vascular system by mobilising proinflammatory cytokines. Thromb Haemost 2012; 108: 730-741.
    Thieme ConnectPubMedSearch in Google Scholar
  • 25 Cerri C, Chimenti D, Conti I. et al. Monocyte/macrophage-derived microparticles up-regulate inflammatory mediator synthesis by human airway epithelial cells. J Immunol 2006; 177: 1975-1980.
    CrossrefPubMedSearch in Google Scholar
  • 26 Liehn EA, Piccinini AM, Koenen RR. et al. A new monocyte chemotactic protein-1/chemokine CC motif ligand-2 competitor limiting neointima formation and myocardial ischaemia/reperfusion injury in mice. J Am Coll Cardiol 2010; 56: 1847-1857.
    CrossrefPubMedSearch in Google Scholar
  • 27 Grohe C, van Eickels M, Wenzel S. et al. Sex-specific differences in ventricular expression and function of parathyroid hormone-related peptide. Cardiovasc Res 2004; 61: 307-316.
    CrossrefPubMedSearch in Google Scholar
  • 28 Cabrera-Fuentes HA, Aslam M, Saffarzadeh M. et al. Internalisation of Bacillus intermedius ribonuclease (BINASE) induces human alveolar adenocarcinoma cell death. Toxicon 2013; 69: 219-226.
    CrossrefPubMedSearch in Google Scholar
  • 29 Inserte J, Barba I, Hernando V. et al. Delayed recovery of intracellular acidosis during reperfusion prevents calpain activation and determines protection in postconditioned myocardium. Cardiovasc Res 2009; 81: 116-122.
    CrossrefPubMedSearch in Google Scholar
  • 30 Abassi ZA, Barac YD, Kostin S. et al. TVP1022 attenuates cardiac remodeling and kidney dysfunction in experimental volume overload-induced congestive heart failure. Circ Heart Fail 2011; 04: 463-473.
    CrossrefPubMedSearch in Google Scholar
  • 31 Rohman MS, Emoto N, Takeshima Y. et al. Decreased mAKAP, ryanodine receptor, and SERCA2a gene expression in mdx hearts. Biochem Biophys Res Commun 2003; 310: 228-235.
    CrossrefPubMedSearch in Google Scholar
  • 32 Simsekyilmaz S, Cabrera-Fuentes HA, Meiler S. et al. Role of extracellular RNA in atherosclerotic plaque formation in mice. Circulation 2014; 129: 598-606.
    CrossrefPubMedSearch in Google Scholar
  • 33 Acharya A, Baek ST, Huang G. et al. The bHLH transcription factor Tcf21 is required for lineage-specific EMT of cardiac fibroblast progenitors. Development 2012; 139: 2139-2149.
    CrossrefPubMedSearch in Google Scholar
  • 34 Vorderwinkler KP, Mair J, Puschendorf B. et al. Cardiac troponin I increases in parallel to cardiac troponin T, creatine kinase and lactate dehydrogenase in effluents from isolated perfused rat hearts after hypoxia-reoxygenation-induced myocardial injury. Clin Chim Acta 1996; 251: 113-117.
    CrossrefPubMedSearch in Google Scholar
  • 35 Fischer S, Cabrera-Fuentes HA, Noll T. et al. Impact of extracellular RNA on endothelial barrier function. Cell Tissue Res. 2014 Epub ahead of print.
    PubMedSearch in Google Scholar
  • 36 Fischer S, Gesierich S, Griemert B. et al. Extracellular RNA liberates tumor necrosis factor-alpha to promote tumor cell trafficking and progression. Cancer Res 2013; 73: 5080-5089.
    CrossrefPubMedSearch in Google Scholar
  • 37 Gilles S, Zahler S, Welsch U. et al. Release of TNF-alpha during myocardial reperfusion depends on oxidative stress and is prevented by mast cell stabilizers. Cardiovasc Res 2003; 60: 608-616.
    CrossrefPubMedSearch in Google Scholar
  • 38 Carpi A, Menabo R, Kaludercic N. et al. The cardioprotective effects elicited by p66(Shc) ablation demonstrate the crucial role of mitochondrial ROS formation in ischaemia/reperfusion injury. Biochim Biophys Acta 2009; 1787: 774-780.
    CrossrefPubMedSearch in Google Scholar
  • 39 Rodrigo R, Prieto JC, Castillo R. Cardioprotection against ischaemia/reperfusion by vitamins C and E plus n-3 fatty acids: molecular mechanisms and potential clinical applications. Clin Sci 2013; 124: 1-15.
    CrossrefPubMedSearch in Google Scholar
  • 40 Bai Y, Muqier Murakami H. et al. Cilostazol protects the heart against ischaemia reperfusion injury in a rabbit model of myocardial infarction: focus on adenosine, nitric oxide and mitochondrial ATP-sensitive potassium channels. Clin Exp Pharmacol Physiol 2011; 38: 658-665.
    CrossrefPubMedSearch in Google Scholar
  • 41 Bonner F, Borg N, Jacoby C. et al. Ecto-5’-nucleotidase on immune cells protects from adverse cardiac remodeling. Circ Res 2013; 113: 301-312.
    CrossrefPubMedSearch in Google Scholar
  • 42 Fischer S, Nishio M, Peters SC. et al. Signaling mechanism of extracellular RNA in endothelial cells. FASEB J 2009; 23: 2100-2109.
    CrossrefPubMedSearch in Google Scholar
  • 43 Fischer S, Preissner KT. Extracellular nucleic acids as novel alarm signals in the vascular system. Mediators of defence and disease. Hamostaseologie 2013; 33: 37-42.
    Thieme ConnectPubMedSearch in Google Scholar
  • 44 Antoniak S, Boltzen U, Eisenreich A. et al. Regulation of cardiomyocyte full-length tissue factor expression and microparticle release under inflammatory conditions in vitro. J Thromb Haemost 2009; 07: 871-878.
    CrossrefPubMedSearch in Google Scholar
  • 45 Gedik N, Heusch G, Skyschally A. Infarct size reduction by cyclosporine A at reperfusion involves inhibition of the mitochondrial permeability transition pore but does not improve mitochondrial respiration. Arch Med Sci 2013; 09: 968-975.
    PubMedSearch in Google Scholar
  • 46 Kleinbongard P, Heusch G, Schulz R. TNFalpha in atherosclerosis, myocardial ischaemia/reperfusion and heart failure. Pharmacol Therap 2010; 127: 295-314.
    CrossrefPubMedSearch in Google Scholar
  • 47 Skyschally A, Gres P, Hoffmann S. et al. Bidirectional role of tumor necrosis factor-alpha in coronary microembolisation: progressive contractile dysfunction versus delayed protection against infarction. Circ Res 2007; 100: 140-146.
    CrossrefPubMedSearch in Google Scholar
  • 48 Kleinbongard P, Schulz R, Heusch G. TNFalpha in myocardial ischaemia/reper-fusion, remodeling and heart failure. Heart Fail Rev 2011; 16: 49-69.
    CrossrefPubMedSearch in Google Scholar
  • 49 Lecour S, Suleman N, Deuchar GA. et al. Pharmacological preconditioning with tumor necrosis factor-alpha activates signal transducer and activator of transcription-3 at reperfusion without involving classic prosurvival kinases (Akt and extracellular signal-regulated kinase). Circulation 2005; 112: 3911-3918.
    CrossrefPubMedSearch in Google Scholar