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The damaging nature of extracellular rna in cardiac ischemia/reperfusion injury: prevention of cardiomyocyte death and heart failure by RNase1

Session Poster session 5

Speaker Hector Alejandro Cabrera-Fuentes

Event : ESC Congress 2015

  • Topic : basic science
  • Sub-topic : Basic Science - Cardiac Diseases
  • Session type : Poster Session

Authors : H A Cabrera-Fuentes (Giessen,DE), M Ruiz-Meana (Barcelona,ES), S Kostin (Bad Nauheim,DE), A Boening (Giessen,DE), S Lecour (Cape Town,ZA), E A Liehn (Aachen,DE), D J Hausenloy (London,GB), D Garcia-Dorado (Barcelona,ES), K D Schlueter (Giessen,DE), K T Preissner (Giessen,DE)

H.A. Cabrera-Fuentes1 , M. Ruiz-Meana2 , S. Kostin3 , A. Boening4 , S. Lecour5 , E.A. Liehn6 , D.J. Hausenloy7 , D. Garcia-Dorado2 , K.D. Schlueter8 , K.T. Preissner1 , 1Justus-Liebig University Giessen, Institute for Biochemistry - Giessen - Germany , 2University Hospital Vall d'Hebron, Laboratorio de Cardiología Experimental - Barcelona - Spain , 3Max Planck Institute for Heart and Lung Research - Bad Nauheim - Germany , 4Justus-Liebig University of Giessen, Department of Cardiovascular Surgery - Giessen - Germany , 5University of Cape Town, Hatter Institute for Cardiovascular Research - Cape Town - South Africa , 6RWTH Aachen University, Institute of Molecular Cardiovascular Research - Aachen - Germany , 7University College London, The Hatter Cardiovascular Institute - London - United Kingdom , 8Justus-Liebig University of Giessen, Institute of Physiology - Giessen - Germany ,

European Heart Journal ( 2015 ) 36 ( Abstract Supplement ), 778-779

During acute myocardial infarction, cardiomyocyte death occurs and has a predominant impact on the quality of life and survival of patients suffering from coronary artery disease, the most eminent single cause of death in industrialized countries. Due to the occlusion of coronary vessels by arteriosclerotic plaque material, largely decreased oxygen supply (termed ischemia) of the myocardium determines the disease outcome. Despite reopening/reperfusion of stenosed vessels, a major organ damage remains. The initial mechanistic triggers of this myocardial “ischemia/reperfusion (I/R) injury” remain greatly unexplained. Here we show that factors from the damaged cardiac tissue itself, in particular extracellular RNA (eRNA) and tumor-necrosis-factor-α (TNF-α), may dictate I/R injury. Following myocardial ischemia/reperfusion (I/R) in mice or I/R induced in the isolated Langendorff rat heart, increased eRNA levels were found together with cardiac injury markers. Likewise, eRNA was released from cardiomyocytes under hypoxia and subsequently induced TNF-α liberation by activation of TNF-α converting enzyme (TACE) and provoked cardiomyocyte death. Conversely, TNF-α promoted eRNA release especially under hypoxia, feeding a vicious cell damaging cycle during I/R. Administration of RNase1 or TAPI (TACE-inhibitor) prevented cell death and myocardial infarction. Likewise, RNase1 significantly reduced I/R-mediated energy exhaustion, opening of mitochondrial permeability transition pores as well as oxidative damage in cardiomyocytes. Finally, a dramatic increase of endogenous vascular RNase1 in human subjects was achieved by inducing non-invasive intermittent limb I/R using an external occluder, thereby supporting the impact of the eRNA/RNase system in remote ischemic preconditioning.

Together, RNase1 as well as inhibition of TACE provide novel therapeutic regimen to interfere with the adverse eRNA-TNF-α interplay and significantly reduce or prevent the pathological outcome of ischemic heart disease. The uncovered fundamental pathomechanisms are likely operative in other organs and tissues as well, such that the proposed interventions offer new concepts for general cytoprotection in medicine.

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