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

Abstract

Background -Despite optimal therapy, the morbidity and mortality of patients presenting

Targeting of Extracellular RNA Reduces Edema Formation and Infarct Size and Improves Survival After Myocardial Infarction in Mice

“…To test the effects of circulating eRNA on endothelial permeability and cardiac edema formation in vivo, we administered exogenous eRNA at a concentration that was comparable to plasma concentrations detected after cardiac ischemia/reperfusion20 or after acute MI, as assessed in this study, via tail vein injection (15 μg/kg). At 4 hours after administration, the mice were euthanatized, and the hearts were weighed immediately after excision and 48 hours later, following storage in a drying chamber at 50°C.…”

“…The eRNA was measured in platelet‐free plasma and may be released by different sources including necrotic cells, apoptotic cells, or activated platelets at the sites of injury. In a previous study of cardiac ischemia/reperfusion injury (IRI), we found cardiomyocytes to be the predominant source of eRNA 20. During MI, high amounts of eRNA are released into the circulation and thus may disrupt the intercellular integrity of the endothelial layer, especially in the direct vicinity of the damaged or necrotic myocardium 23…”

Extracellular Ribonucleic Acids (RNA) Enter the Stage in Cardiovascular Disease

“…20 Accumulated eRNA in atherosclerotic plaques may not only be derived from damaged or apoptotic cells but also be released on inflammatory cell activation, as supported by findings showing that tumor necrosis factor-α (TNF-α) stimulation of smooth muscle cells (SMCs) provoked the release of eRNA in vitro. 20 The exact nature of eRNA species deposited under these conditions remains to be defined. In addition, the conditions and stimuli triggering the release of eRNA in atherosclerosis will need to be addressed in further detail in future studies as well.…”

“…18 Increased levels of circulating eRNA are for instance detected not only in patients with tumors, sepsis, or lung fibrosis 17,19 but also after arterial injury, in atherosclerosis-prone mice with myocardial infarction and ischemia-reperfusion (I/R) injury. 20 The proportion of different forms of released eRNA seems to correspond to the quantities of RNA species found inside cells, whereas the liberation of certain miRNAs has been linked to the cell type-specific generation of exosomes or microvesicles. Although not systematically investigated yet, the entity of released eRNA, its composition, and its potential association with microvesicles largely depend on the investigated cell type, the particular stimulus or type of cell injury, and the (patho)physiological context.…”

“…For instance, elevated levels of eRNA in plasma collected from perfusates during I/R of isolated rat hearts in response to hypoxia were primarily associated with microvesicles, whereas the majority of eRNA in unstimulated cell-free plasma represented the typical 28S/18S pattern of rRNA. 18,20 Likewise, damage of cells and unregulated cell death result in (passive) liberation of appreciable amounts of rRNA as the predominant RNA species. 21 In addition, long noncoding RNAs confer interactions outside and inside cells, 22 and functional and signaling properties of such high-molecular weight RNA species in vascular cells were recently uncovered in part by our group.…”