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

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.