Extracellular nucleic acids in immunity and cardiovascular responses: between alert and disease

 

 Buy Article Permissions and Reprints

Summary

Severe inflammatory complications are a potential consequence in patients with predetermined conditions of infections, pulmonary diseases, or cardiovascular disorders. Notably, the amplitude of the inflammatory response towards these complications can dictate the disease progression and outcome. During the recent years, evidence from basic research as well as from clinical studies has identified self-extracellular nucleic acids as important players in the crosstalk between immunity and cardiovascular diseases. These stress- or injury-induced endogenous polymeric macromolecules not only serve as “alarmins” or “Danger-associated molecular patterns” (DAMPs), but their functional repertoire goes far beyond such activities in innate immunity. In fact, (patho-) physiological functions of self-extracellular DNA and RNA are associated and in many cases causally related to arterial and venous thrombosis, atherosclerosis, ischemia-reperfusion injury or tumour progression. Yet, the underlying molecular mechanisms are far from being completely understood. Interestingly enough, however, novel antagonistic approaches in vitro and in vivo, particularly using natural endonucleases or synthetic nucleic acid binding polymers, appear to be promising and safe therapeutic options for future studies. The aim of this review article is to provide an overview of the current state of (patho-) physiological functions of self-extracellular nucleic acids with special emphasis on their role as beneficial / alerting or adverse / damaging factors in connection with immune responses, inflammation, thrombosis, and cardiovascular diseases.

• References

• 1 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13: 34-45.
  CrossrefPubMedGoogle Scholar
• 2 Roers A. et al. Recognition of endogenous nucleic acids by the innate immune system. Immunity 2016; 44: 739-754.
  CrossrefPubMedGoogle Scholar
• 3 Sirois CM. et al. RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA. J Exp Med 2013; 210: 2447-2463.
  CrossrefPubMedGoogle Scholar
• 4 Bertheloot D. et al. RAGE enhances TLR responses through binding and internalization of RNA. J Immunol 2016; 197: 4118-4126.
  CrossrefPubMedGoogle Scholar
• 5 Collins LV. et al. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J Leukoc Biol 2004; 75: 995-1000.
  CrossrefPubMedGoogle Scholar
• 6 Fischer S, Preissner KT. Extracellular nucleic acids as novel alarm signals in the vascular system. Mediators of defence and disease. Haemostaseologie 2013; 33: 37-42.
  PubMedGoogle Scholar
• 7 Zhang X, Soldati T. Of Amoebae and men: Extracellular DNA traps as an ancient cell-intrinsic defense mechanism. Front Immunol 2016; 7: 269.
  PubMedGoogle Scholar
• 8 Zhang X. et al. Social amoebae trap and kill bacteria by casting DNA nets. Nat Commun 2016; 7: 10938.
  CrossrefPubMedGoogle Scholar
• 9 Altincicek B. et al. Host-derived extracellular nucleic acids enhance innate immune responses, induce coagulation, and prolong survival upon infection in insects. J Immunol 2008; 181: 2705-2712.
  CrossrefPubMedGoogle Scholar
• 10 Stokes BA. et al. Bacterial and fungal pattern recognition receptors in homologous innate signaling pathways of insects and mammals. Front Microbiol 2015; 6: 19.
  PubMedGoogle Scholar
• 11 Brinkmann V. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532-1535.
  CrossrefPubMedGoogle Scholar
• 12 Saffarzadeh M, Preissner KT. Fighting against the dark side of neutrophil extracellular traps in disease: manoeuvres for host protection. Curr Opin Hematol 2013; 20: 3-9.
  CrossrefPubMedGoogle Scholar
• 13 Sorensen OE, Borregaard N. Neutrophil extracellular traps - the dark side of neutrophils. J Clin Invest 2016; 126: 1612-1620.
  CrossrefPubMedGoogle Scholar
• 14 Desai J. et al. Matters of life and death. How neutrophils die or survive along NET release and is “NETosis„ = necroptosis?. Cell Mol Life Sci 2016; 73: 2211-2219.
  CrossrefPubMedGoogle Scholar
• 15 Yang H. et al. New Insights into Neutrophil Extracellular Traps: Mechanisms of Formation and Role in Inflammation. Front Immunol 2016; 7: 302.
  PubMedGoogle Scholar
• 16 Saffarzadeh M. et al. Characterization of rapid neutrophil extracellular trap formation and its cooperation with phagocytosis in human neutrophils. Discoveries 2014; 2: e19
  CrossrefPubMedGoogle Scholar
• 17 Yipp BG, Kubes P. NETosis: how vital is it?. Blood 2013; 122: 2784-2794.
  CrossrefPubMedGoogle Scholar
• 18 Masuda S. et al. NETosis markers: Quest for specific, objective, and quantitative markers. Clin Chim Acta 2016; 459: 89-93.
  CrossrefPubMedGoogle Scholar
• 19 von Kockritz-Blickwede M. et al. Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood 2008; 111: 3070-3080.
  CrossrefPubMedGoogle Scholar
• 20 Boe DM. et al. Extracellular traps and macrophages: new roles for the versatile phagocyte. J Leukoc Biol 2015; 97: 1023-1035.
  CrossrefPubMedGoogle Scholar
• 21 Yousefi S. et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat Med 2008; 14: 949-953.
  CrossrefPubMedGoogle Scholar
• 22 Jiang D. et al. Suppression of Neutrophil-Mediated Tissue Damage: A Novel Skill of Mesenchymal Stem Cells. Stem Cells 2016; 34: 2393-2406.
  CrossrefPubMedGoogle Scholar
• 23 Mangold A. et al. Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ Res 2015; 116: 1182-1192.
  CrossrefPubMedGoogle Scholar
• 24 Urban CF. et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans . PLoS Pathog 2009; 5: e1000639.
  CrossrefPubMedGoogle Scholar
• 25 Mandel P, Metais P. Les acides nucléiques du plasma sanguin chez l’homme. C R Seances Soc Biol Fil. 1948; 142: 241-243.
  PubMedGoogle Scholar
• 26 Liaw PC. et al. DAMP and DIC: The role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. Blood Rev 2016; 30: 257-261.
  CrossrefPubMedGoogle Scholar
• 27 Gauthier VJ. et al. Blood clearance kinetics and liver uptake of mono-nucleosomes in mice. J Immunol. 1996; 156: 1151-1156.
  PubMedGoogle Scholar
• 28 Zeerleder S. et al. Elevated nucleosome levels in systemic inflammation and sepsis. Crit Care Med 2003; 31: 1947-1951.
  CrossrefPubMedGoogle Scholar
• 29 Marsman G. et al. Extracellular histones, cell-free DNA, or nucleosomes: differences in immunostimulation. Cell Death Dis 2016; 7: e2518
  CrossrefPubMedGoogle Scholar
• 30 Schwarzenbach H. et al. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 2011; 11: 426-437.
  CrossrefPubMedGoogle Scholar
• 31 Saukkonen K. et al. Cell-free plasma DNA as a predictor of outcome in severe sepsis and septic shock. Clin Chem 2008; 54: 1000-1007.
  CrossrefPubMedGoogle Scholar
• 32 Dwivedi DJ. et al. Prognostic utility and characterization of cell-free DNA in patients with severe sepsis. Crit Care 2012; 16: R151.
  CrossrefPubMedGoogle Scholar
• 33 Clementi A. et al. The role of cell-free plasma DNA in critically ill patients with sepsis. Blood Purif 2016; 41: 34-40.
  CrossrefPubMedGoogle Scholar
• 34 Siljan WW. et al. Circulating cell-free DNA is elevated in community-acquired bacterial pneumonia and predicts short-term outcome. J Infect 2016; 73: 383-386.
  CrossrefPubMedGoogle Scholar
• 35 Alix-Panabières C, Pantel K. Clinical applications of circulating tumor cells and circulating tumor DNA as liquid biopsy. Cancer Discov 2016; 6: 479-491.
  CrossrefPubMedGoogle Scholar
• 36 Cheng OZ, Palaniyar N. NET balancing: a problem in inflammatory lung diseases. Front Immunol 2013; 4: 1.
  PubMedGoogle Scholar
• 37 Folkesson A. et al. Adaptation of Pseudomonas aeruginosa to the cystic fibrosis airway: an evolutionary perspective. Nat Rev Microbiol 2012; 10: 841-851.
  CrossrefPubMedGoogle Scholar
• 38 Bhongir RK. et al. DNA-fragmentation is a source of bactericidal activity against Pseudomonas aeruginosa. Biochem J 2016; 474: 411-425.
  PubMedGoogle Scholar
• 39 Gaipl US. et al. Cooperation between C1q and DNase I in the clearance of necrotic cell-derived chromatin. Arthritis Rheum 2004; 50: 640-649.
  CrossrefPubMedGoogle Scholar
• 40 Zeerleder S. et al. Nucleosome-releasing factor: a new role for factor VII-activating protease (FSAP). FASEB J 2008; 22: 4077-4084.
  CrossrefPubMedGoogle Scholar
• 41 Nakazawa F. et al. Extracellular RNA is a natural cofactor for the (auto-)activation of Factor VII-activating protease (FSAP). Biochem J 2005; 385: 831-838.
  CrossrefPubMedGoogle Scholar
• 42 Stephan F. et al. Cooperation of factor VII-activating protease and serum DNase I in the release of nucleosomes from necrotic cells. Arthritis Rheumatol 2014; 66: 686-693.
  CrossrefPubMedGoogle Scholar
• 43 Stephan F. et al. Complexes of factor VII-activating protease with plasminogen activator inhibitor-1 in human sepsis. Thromb Haemost 2014; 112: 219-221.
  Article in Thieme ConnectPubMedGoogle Scholar
• 44 Stephan F. et al. Activation of factor VII-activating protease in human inflammation: a sensor for cell death. Crit Care 2011; 15: R110.
  CrossrefPubMedGoogle Scholar
• 45 Pisetsky DS. The origin and properties of extracellular DNA: from PAMP to DAMP. Clin Immunol 2012; 144: 32-40.
  CrossrefPubMedGoogle Scholar
• 46 Sirois CM. et al. RAGE is a nucleic acid receptor that promotes inflammatory responses to DNA. J Exp Med 2013; 210: 2447-2463.
  CrossrefPubMedGoogle Scholar
• 47 Ulm C. et al. Soluble polysialylated NCAM: a novel player of the innate immune system in the lung. Cell Mol Life Sci 2013; 70: 3695-3708.
  CrossrefPubMedGoogle Scholar
• 48 Westman J. et al. Treatment with p33 curtails morbidity and mortality in a histone-induced murine shock model. J Innate Immun 2014; 6: 819-830.
  CrossrefPubMedGoogle Scholar
• 49 Xu J. et al. Extracellular histones are major mediators of death in sepsis. Nat Med 2009; 15: 1318-1321.
  CrossrefPubMedGoogle Scholar
• 50 Westman J. et al. Extracellular histones induce chemokine production in whole blood ex vivo and leukocyte recruitment in vivo . PLoS Pathog 2015; 11: e1005319.
  CrossrefPubMedGoogle Scholar
• 51 Park JS. et al. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 2004; 279: 7370-7377.
  CrossrefPubMedGoogle Scholar
• 52 Dumitriu IE. et al. Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products. J Immunol 2005; 174: 7506-7515.
  CrossrefPubMedGoogle Scholar
• 53 Xu J. et al. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol 2011; 187: 2626-2631.
  CrossrefPubMedGoogle Scholar
• 54 Allam R. et al. Extracellular histones in tissue injury and inflammation. J Mol Med 2014; 92: 465-472.
  CrossrefPubMedGoogle Scholar
• 55 Linkermann A, Green DR. Necroptosis. N Engl J Med 2014; 370: 455-465.
  CrossrefPubMedGoogle Scholar
• 56 Fischer S. et al. Impact of extracellular RNA on endothelial barrier function. Cell Tissue Res 2014; 355: 635-645.
  CrossrefPubMedGoogle Scholar
• 57 Wieczorek AJ. et al. Isolation and characterization of an RNA-proteolipid complex associated with the malignant state in humans. Proc Natl Acad Sci USA 1985; 82: 3455-3459.
  CrossrefPubMedGoogle Scholar
• 58 Zernecke A, Preissner KT. Extracellular Ribonucleic Acids (RNA) enter the stage in cardiovascular disease. Circ Res 2016; 118: 469-479.
  CrossrefPubMedGoogle Scholar
• 59 de Candia P. et al. Extracellular RNAs: A Secret Arm of Immune System Regulation. J Biol Chem 2016; 291: 7221-7228.
  CrossrefPubMedGoogle Scholar
• 60 Boosani CS, Agrawal DK. Epigenetic regulation of innate immunity by microRNAs. Antibodies 2016; 5
  PubMedGoogle Scholar
• 61 Raisch J. et al. Role of microRNAs in the immune system, inflammation and cancer. World J Gastroenterol 2013; 19: 2985-2996.
  CrossrefPubMedGoogle Scholar
• 62 Garo LP, Murugaiyan G. Contribution of MicroRNAs to autoimmune diseases. Cell Mol Life Sci 2016; 73: 2041-2051.
  CrossrefPubMedGoogle Scholar
• 63 Chhatwal GS, Preissner KT. Extracellular matrix and host cell surfaces: potential sites of pathogen interaction. In: Cellular Microbiology. 2005. Washington DC: 2th ed.. ASM Press; pp. 87-104.
  Google Scholar
• 64 Zakrzewicz D. et al. Host-derived extracellular RNA promotes adhesion of Streptococcus pneumoniae to endothelial and epithelial cells. Sci Rep 2016; 6: 37758.
  CrossrefPubMedGoogle Scholar
• 65 Balint Z. et al. Double-stranded RNA attenuates the barrier function of human pulmonary artery endothelial cells. PLoS One 2014; 8: e63776.
  PubMedGoogle Scholar
• 66 Fischer S. et al. Extracellular RNA mediates endothelial-cell permeability via vascular endothelial growth factor. Blood 2007; 110: 2457-2465.
  CrossrefPubMedGoogle Scholar
• 67 Fischer S. et al. Signaling mechanism of extracellular RNA in endothelial cells. FASEB J 2009; 23: 2100-2109.
  CrossrefPubMedGoogle Scholar
• 68 Fischer S. et al. Extracellular RNA promotes leukocyte recruitment in the vascular system by mobilising proinflammatory cytokines. Thromb Haemost 2012; 108: 730-741.
  Article in Thieme ConnectPubMedGoogle Scholar
• 69 Cabrera-Fuentes HA. et al. RNase1 prevents the damaging interplay between extracellular RNA and tumour necrosis factor-a in cardiac ischaemia/reperfusion injury. Thromb Haemost 2014; 112: 1110-1119.
  Article in Thieme ConnectPubMedGoogle Scholar
• 70 Simsekyilmaz S. et al. Role of extracellular RNA in atherosclerotic plaque formation in mice. Circulation 2014; 129: 598-606.
  CrossrefPubMedGoogle Scholar
• 71 Zimmermann-Geller B. et al. Influence of Extracellular RNAs, released by rheumatoid arthritis synovial fibroblasts, on their adhesive and invasive properties. J Immunol 2016; 197: 2589-2597.
  CrossrefPubMedGoogle Scholar
• 72 Cabrera-Fuentes HA. et al. Regulation of monocyte/macrophage polarisation by extracellular RNA. Thromb Haemost 2015; 113: 473-481.
  Article in Thieme ConnectPubMedGoogle Scholar
• 73 Fischer S. et al. Extracellular RNA liberates tumor necrosis factor-a to promote tumor cell trafficking and progression. Cancer Res 2013; 73: 5080-5089.
  CrossrefPubMedGoogle Scholar
• 74 Scheller J. et al. ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol 2011; 32: 380-387.
  CrossrefPubMedGoogle Scholar
• 75 Stachon P. et al. Extracellular ATP induces vascular inflammation and atherosclerosis via purinergic receptor Y2 in mice. Arterioscler Thromb Vasc Biol 2016; 36: 1577-1586.
  CrossrefPubMedGoogle Scholar
• 76 Chen G. et al. Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood 2014; 123: 3818-3827.
  CrossrefPubMedGoogle Scholar
• 77 Maugeri N. et al. Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J Thromb Haemost 2014; 12: 2074-2088.
  CrossrefPubMedGoogle Scholar
• 78 Bhagirath VC. et al. Comparison of the proinflammatory and procoagulant properties of nuclear, mitochondrial, and bacterial DNA. Shock 2015; 44: 265-271.
  CrossrefPubMedGoogle Scholar
• 79 Gould TJ. et al. Cell-free DNA modulates clot structure and impairs fibrinolysis in sepsis. Arterioscler Thromb Vasc Biol 2015; 35: 2544-2553.
  CrossrefPubMedGoogle Scholar
• 80 Clark SR. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13: 463-469.
  CrossrefPubMedGoogle Scholar
• 81 Massberg S. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16: 887-896.
  CrossrefPubMedGoogle Scholar
• 82 Fuchs TA. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 2010; 107: 15880-15885.
  CrossrefPubMedGoogle Scholar
• 83 von Bruhl ML. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209: 819-835.
  CrossrefPubMedGoogle Scholar
• 84 Schulz C. et al. Crossroads of coagulation and innate immunity: the case of deep vein thrombosis. J Thromb Haemost 2013; 11 (Suppl. 01) 233-241.
  CrossrefPubMedGoogle Scholar
• 85 Caudrillier A. et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J Clin Invest 2012; 122: 2661-2671.
  CrossrefPubMedGoogle Scholar
• 86 Gardiner EE, Andrews RK. Neutrophil extracellular traps (NETs) and infection-related vascular dysfunction. Blood Rev 2012; 26: 255-259.
  CrossrefPubMedGoogle Scholar
• 87 Tadie JM. et al. HMGB1 promotes neutrophil extracellular trap formation through interactions with Toll-like receptor 4. Am J Physiol Lung Cell Mol Physiol 2013; 304: L342-L349.
  CrossrefPubMedGoogle Scholar
• 88 Smith SA, Morrissey JH. Polyphosphate: A new player in the field of hemostasis. Curr Opin Hematol 2014; 21: 388-394.
  CrossrefPubMedGoogle Scholar
• 89 Saffarzadeh M, Preissner KT. Moonlighting proteins dictate the crosstalk between thrombosis and innate immunity. J Thromb Haemost 2014; 12: 2070-2073.
  CrossrefPubMedGoogle Scholar
• 90 Mitroulis I. et al. Neutrophil extracellular trap formation is associated with IL-1ß and autophagy-related signaling in gout. PLoS One 2011; 6: e29318.
  CrossrefPubMedGoogle Scholar
• 91 Oehmcke S. et al. Activation of the human contact system on neutrophil extracellular traps. J Innate Immun 2009; 1: 225-230.
  CrossrefPubMedGoogle Scholar
• 92 Stakos DA. et al. Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction. Eur Heart J 2015; 36: 1405-1414.
  CrossrefPubMedGoogle Scholar
• 93 Ge L. et al. Neutrophil extracellular traps in ischaemia-reperfusion injury-induced myocardial no-reflow: therapeutic potential of DNase-based reperfusion strategy. Am J Physiol Heart Circ Physiol 2015; 308: H500-H509.
  CrossrefPubMedGoogle Scholar
• 94 McDonald B. et al. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 2012; 12: 324-333.
  CrossrefPubMedGoogle Scholar
• 95 Saffarzadeh M. et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLoS One 2012; 7: e32366.
  CrossrefPubMedGoogle Scholar
• 96 Brill A. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 2012; 10: 136-144.
  CrossrefPubMedGoogle Scholar
• 97 De Meyer SF. et al. Extracellular chromatin is an important mediator of ischaemic stroke in mice. Arterioscler Thromb Vasc Biol 2012; 32: 1884-1891.
  CrossrefPubMedGoogle Scholar
• 98 Varju I. et al. DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment. Thromb Haemost 2015; 113: 1289-1298.
  Article in Thieme ConnectPubMedGoogle Scholar
• 99 Demers M. et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci USA 2012; 109: 13076-13081.
  CrossrefPubMedGoogle Scholar
• 100 Cochrane CG, Griffin JH. The biochemistry and pathophysiology of the contact system of plasma. Adv Immunol 1982; 33: 241-306.
  PubMedGoogle Scholar
• 101 Hojima Y. et al. In vitro activation of the contact (Hageman factor) system of plasma by heparin and chondroitin sulfate E. Blood 1984; 63: 1453-1459.
  CrossrefPubMedGoogle Scholar
• 102 Colman RW, Schmaier AH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997; 90: 3819-3843.
  PubMedGoogle Scholar
• 103 Long AT. et al. Contact system revisited: an interface between inflammation, coagulation, and innate immunity. J Thromb Haemost 2016; 14: 427-437.
  CrossrefPubMedGoogle Scholar
• 104 Kannemeier C. et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci USA 2007; 104: 6388-6393.
  CrossrefPubMedGoogle Scholar
• 105 Muller F. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139: 1143-1156.
  CrossrefPubMedGoogle Scholar
• 106 Maas C. et al. Misfolded proteins activate factor XII in humans, leading to kallikrein formation without initiating coagulation. J Clin Invest 2008; 118: 3208-3218.
  PubMedGoogle Scholar
• 107 Renne T. et al. In vivo roles of factor XII. Blood 2012; 120: 4296-4303.
  CrossrefPubMedGoogle Scholar
• 108 Labberton L. et al. New agents for thromboprotection. A role for factor XII and XIIa inhibition. Haemostaseologie 2015; 35: 338-350.
  PubMedGoogle Scholar
• 109 Gansler J. et al. Structural requirements for the procoagulant activity of nucleic acids. PLoS One 2012; 7: e50399.
  CrossrefPubMedGoogle Scholar
• 110 Paul A. et al. Aptamers influence the hemostatic system by activating the intrinsic coagulation pathway in an in vitro Chandler-Loop model. Clin Appl Thromb Hemost 2010; 16: 161-169.
  CrossrefPubMedGoogle Scholar
• 111 Vu TT. et al. Arterial thrombosis is accelerated in mice deficient in histidine-rich glycoprotein. Blood 2015; 125: 2712-2719.
  CrossrefPubMedGoogle Scholar
• 112 Subramaniam S. et al. Defective thrombus formation in mice lacking endogenous factor VII activating protease (FSAP). Thromb Haemost 2015; 113: 870-880.
  Article in Thieme ConnectPubMedGoogle Scholar
• 113 Parahuleva MS. et al. Circulating factor VII activating protease (FSAP) is associated with clinical outcome in acute coronary syndrome. Circ J 2012; 76: 2653-2661.
  CrossrefPubMedGoogle Scholar
• 114 Kanse SM. et al. Factor VII-activating protease (FSAP): vascular functions and role in atherosclerosis. Thromb Haemost 2008; 99: 286-289.
  Article in Thieme ConnectPubMedGoogle Scholar
• 115 Boon RA. et al. Atheroprotective mechanisms of shear stress-regulated microRNAs. Thromb Haemost 2012; 108: 616-620.
  Article in Thieme ConnectPubMedGoogle Scholar
• 116 Fischer S. et al. Impact of extracellular RNA on endothelial barrier function. Cell Tissue Res 2014; 355: 635-645.
  CrossrefPubMedGoogle Scholar
• 117 Hopkins PN. Molecular biology of atherosclerosis. Physiol Rev 2013; 93: 1317-1542.
  CrossrefPubMedGoogle Scholar
• 118 Stieger P. et al. Targeting of extracellular RNA reduces edema formation and infarct size and improves survival after myocardial infarction in mice. J Am Heart Assoc 2017 in press
  PubMedGoogle Scholar
• 119 Zhang XY. et al. RNase attenuates acute lung injury induced by ischaemia-reperfusion in mice. Int Immunopharmacol 2016; 40: 288-293.
  CrossrefPubMedGoogle Scholar
• 120 Chen C. et al. Role of extracellular RNA and TLR3-Trif signaling in myocardial ischaemia-reperfusion injury. J Am Heart Assoc 2014; 3: e000683.
  CrossrefPubMedGoogle Scholar
• 121 Feng Y. et al. Cardiac RNA induces inflammatory responses in cardiomyocytes and immune cells via Toll-like receptor 7 signaling. J Biol Chem 2015; 290: 26688-26698.
  CrossrefPubMedGoogle Scholar
• 122 Lee J. et al. Nucleic acid-binding polymers as anti-inflammatory agents. Proc. Natl Acad Sci USA 2011; 108: 14055-14060.
  CrossrefPubMedGoogle Scholar
• 123 Jain S. et al. Nucleic acid scavengers inhibit thrombosis without increasing bleeding. Proc Natl Acad Sci USA 2012; 109: 12938-12943.
  CrossrefPubMedGoogle Scholar