期刊
THROMBOSIS AND HAEMOSTASIS
卷 112, 期 6, 页码 1110-1119出版社
GEORG THIEME VERLAG KG
DOI: 10.1160/TH14-08-0703
关键词
Inflammatory mediators; ischaemic heart disease; cytokines; cardiology
资金
- German Research Council (DFG
- Bonn, Germany) within the International Graduate School PROMISE (Giessen-Barcelona) [IRTG-1566]
- Excellence Cluster Cardiopulmonary System (ECCPS, Giessen)
- DFG-Research Group Chemokines and Adhesion Molecules in Cardiovascular Pathogenesis [FOR 809]
- University Hospital-Giessen-Marburg Cooperative Grant
- Interdisciplinary Centre for Clinical Research (IZKF
- Aachen, Germany)
- University of Cape Town, South Africa
- Ramon y Cajal Fellowship (Barcelona, Spain)
- British Heart Foundation Senior Clinical Research Fellowship [FS/10/039/28270]
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 alpha (TNF-alpha), 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-alpha. Moreover, TNF-alpha 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 1 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-alpha interplay and significantly reduces or prevents the pathological out-come of ischaemic heart disease.
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