title: RNase1 prevents the damaging interplay between extracellular RNA and tumour necrosis factor-α in cardiac ischaemia/reperfusion injury.
abstract: 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.
authors.forename: H A
authors.initials: HA
authors.lastname: Cabrera-Fuentes
authors.forename: M
authors.initials: M
authors.lastname: Ruiz-Meana
authors.forename: S
authors.initials: S
authors.lastname: Simsekyilmaz
authors.forename: S
authors.initials: S
authors.lastname: Kostin
authors.forename: J
authors.initials: J
authors.lastname: Inserte
authors.forename: M
authors.initials: M
authors.lastname: Saffarzadeh
authors.forename: S P
authors.initials: SP
authors.lastname: Galuska
authors.forename: V
authors.initials: V
authors.lastname: Vijayan
authors.forename: I
authors.initials: I
authors.lastname: Barba
authors.forename: G
authors.initials: G
authors.lastname: Barreto
authors.forename: S
authors.initials: S
authors.lastname: Fischer
authors.forename: G
authors.initials: G
authors.lastname: Lochnit
authors.forename: O N
authors.initials: ON
authors.lastname: Ilinskaya
authors.forename: E
authors.initials: E
authors.lastname: Baumgart-Vogt
authors.forename: A
authors.initials: A
authors.lastname: Böning
authors.forename: S
authors.initials: S
authors.lastname: Lecour
authors.forename: D J
authors.initials: DJ
authors.lastname: Hausenloy
authors.forename: E A
authors.initials: EA
authors.lastname: Liehn
authors.forename: D
authors.initials: D
authors.lastname: Garcia-Dorado
authors.forename: K-D
authors.initials: KD
authors.lastname: Schlüter
authors.affiliation: Klaus T. Preissner, PhD, Depart. Biochemistry, Medical School, Justus-Liebig-Universität, Friedrichstrasse 24, 35392 Giessen, Germany, Tel.: +49 641 994 7500; Fax: +49 641 994 7509, E-mail: klaus.t.preissner@biochemie.med.uni-giessen.de.
authors.forename: K T
authors.initials: KT
authors.lastname: Preissner
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D019898:Autocrine Communication / Q000187:drug effects*; D015687:Cell Hypoxia; D019610:Cytoprotection; D004195:Disease Models, Animal; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D012260:Ribonucleases / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D012260:Ribonucleases
keywords: Inflammatory mediators; cardiology; cytokines; ischaemic heart disease