RESULTS:
1 - 2 of 2 for ""Extracellular RNA""
Extracellular RNA, a Potential Drug Target for Alleviating Atherosclerosis, Ischemia/Reperfusion Injury and Organ Transplantation
Extracellular RNA (eRNA) composed of mainly rRNA e.g. released upon cell injury has previously been shown to have three main detrimental functions in the context of cardiovascular disease: (1) to promote tissue edema by activating the VEGF signal transduction cascade disrupting endothelial tight junctions and increasing intercellular permeability; (2) to induce thrombus formation by activating the contact phase system of intrinsic blood coagulation; and (3) to increase inflammation by stimulating leukocyte adhesion and transmigration and the mobilization of pro-inflammatory cytokines. This review proposes eRNA to be a possible new drug target in cardiovascular disease. The effects of eRNA could potentially be limited by enhancing its degradation through the naturally occurring ribonuclease RNase. In acute settings such as transplantation or ischemia/reperfusion injury after myocardial infarction this could be achieved by administering RNase intravenously; however in chronic situations such as atherosclerosis a new orally administrable chemical compound e.g. blocking the endogenous RNase inhibitor might be developed. In ischemia/reperfusion injury as well as in acute graft rejection such an intervention would likely reduce edema thrombosis inflammation and cellular damage and hence improve survival. In atherosclerosis antagonizing the RNase inhibitor would presumably reduce inflammation and slow plaque growth. Crucially toxicological examinations of RNase administration did not find any adverse side effects denoting it as potentially safe and well-tolerated. Therefore eRNA appears to be a promising drug target in cardiovascular disease and further investigations are required for the possible clinical use of an agent limiting its activity.
The Role of Extracellular Nucleic Acids in Rheumatoid Arthritis
Chronic inflammation synovial hyperplasia and local hypoxia lead to synovial cell activation causing severe joint damage in chronic-inflammatory rheumatoid arthritis (RA). The proinflammatory and joint-destructive property of the increased release of extracellular nucleic acids has been demonstrated for extracellular mitochondrial DNA and oxidized DNA using an arthritis model. Microparticles derived from different cells are able to transport nucleic acids to distant cells and promote cellular activation in RA. In addition extracellular RNA (eRNA) is present in the RA synovial lining layer whereas eDNA could be detected in various areas of synovial tissue when compared to controls. The main source of eDNA is the formation of neutrophil extracellular traps (NETs) due to increased amounts of activated neutrophils in the synovial fluid in RA. A central cell type of joint destruction is the activated RA synovial fibroblast (RASF) characterized by increased production of proinflammatory factors matrix-degrading enzymes enhanced matrix adhesion and cell migration. eRNA was shown to be released by RASF under hypoxia and RNase activity was increased in RA synovial fluid. In vitro RNase-mediated reduction of eRNA decreased RASF adhesion to cartilage but not proliferation or adhesion to endothelial cells. In vivo RNase1 treatment reduced RASF invasion into cartilage. Therefore extracellular nucleic acids induced by (auto)immune responses in RA appear to promote inflammation and local joint destruction.