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

Abstract

Inflammatory and ischemic cardiovascular diseases, especially atherosclerosis and myocardial infarction, remain the number one cause of death in the Western world, whereas the therapeutic options currently available are still limited. Several recent findings have indicated that nucleic acids, particularly extracellular ribosomal RNA and micro-RNAs, significantly contribute to the adverse outcome of atherosclerosis, myocardial infarction, and other cardiovascular diseases. Extracellular RNAs act as novel danger-associated molecular pattern signals and potent cofactors in cardiovascular inflammation and thrombosis, particularly when accumulating in the extracellular space under tissue-damaging or pathological conditions. In this concise review article, the different entities of extracellular RNAs, their cellular sources, and their putative functional contribution to the pathogenesis of cardiovascular diseases will be discussed. In fact, it remains a tightrope walk for these polyanionic molecules outside cells to promote defense reactions on the one side but to provoke cardiovascular disease development on the other side, dependent on their concentration, the environmental conditions, and the cellular stimuli engaged. Thus, we will discuss the mechanisms and cellular responses by which extracellular RNAs operate between defense and disease. Finally, natural counteracting molecules, such as RNase1, will be focused on to elaborate their protective functions in the context of inflammatory and ischemic cardiovascular diseases with the possibility to apply them as novel interventional strategies.

Ischemia/Reperfusion

“…In addition to regulating the expression of mRNAs and thus protein expression within cells, miRNAs can also be secreted to the extracellular compartment, as can ribosomal RNA. These extracellular RNAs adversely affect outcomes in I/R by acting as damage-associated molecular patterns (DAMPs) and as cofactors for activation of inflammatory cascades and thrombosis (899). Indeed, myocardial I/R is associated with significant release of RNA, including several miRNAs, primarily by cardiac myocytes, although endothelial cells, fibroblasts, and vascular smooth muscle cells also contribute (105, 133).…”

Immune cells in repair of the infarcted myocardium

“…Cardiomyocyte‐derived HMGB1 may serve as an important early stimulus, triggering the inflammatory reaction following myocardial infarction. IL‐1α, extracellular RNAs, HSPs and members of the S100 family may also contribute to activation of myocardial inflammation. Immune cells may be important cellular targets of alarmins in the infarcted myocardium.…”

Comparative functional analysis of ribonuclease 1 homologs: molecular insights into evolving vertebrate physiology

“…Recent work has identified extracellular RNA (exRNA) as a heterogeneous class of secreted cofactors in bodily fluids that can contribute to coagulation, blood vessel permeability, cell–cell signaling, tumor progression, and inflammation. They can be single or double-stranded, and can originate from internal cells or from antigenic sources, such as invading bacteria or viruses [71, 72]. As the only known ribonuclease in bodily fluids with high, nonspecific ribonucleolytic activity, RNase 1 might be a natural regulator of exRNA.…”

“…Significantly, we found that some mammalian RNase 1 homologs not only degrade dsRNA efficiently, but also enter endosomes readily, potentially mediated by interactions with cell-surface glycans. Human RNase 1, in particular, might be especially well adapted to degrade antigenic exRNA both within endosomes and in the extracellular space, suggesting an important role for human RNase 1 in regulating processes like coagulation and inflammation [72]. The amino acid sequence of human RNase 1 is identical to that of the Neanderthal enzyme [74], indicative of its biological role being established in a common ancestor at least 550,000 years ago.…”