Septic cardiomyopathy is a life-threatening organ dysfunction caused by sepsis. Ribonuclease 1 (RNase 1) belongs to a group of host-defense peptides that specifically cleave extracellular RNA (eRNA). The activity of RNase 1 is inhibited by ribonuclease-inhibitor 1 (RNH1). However, the role of RNase 1 in septic cardiomyopathy and associated cardiac apoptosis is completely unknown. Here, we show that sepsis resulted in a significant increase in RNH1 and eRNA serum levels compared with those of healthy subjects. Treatment with RNase 1 resulted in a significant decrease of apoptosis, induced by the intrinsic pathway, and TNF expression in murine cardiomyocytes exposed to either necrotic cardiomyocytes or serum of septic patients for 16 hours. Additionally, treatment of septic mice with RNase 1 resulted in a reduction in cardiac apoptosis, TNF expression, and septic cardiomyopathy. These data demonstrate that eRNA plays a crucial role in the pathophysiology of the organ (cardiac) dysfunction in sepsis and that RNase and RNH1 may be new therapeutic targets and/or strategies to reduce the cardiac injury and dysfunction caused by sepsis.
Elisabeth Zechendorf, Caroline E. O’Riordan, Lara Stiehler, Natalie Wischmeyer, Fausto Chiazza, Debora Collotta, Bernd Denecke, Sabrina Ernst, Gerhard Müller-Newen, Sina M. Coldewey, Bianka Wissuwa, Massimo Collino, Tim-Philipp Simon, Tobias Schuerholz, Christian Stoppe, Gernot Marx, Christoph Thiemermann, Lukas Martin
RNase 1 treatment or TLR3 inhibition results in decrease of caspase-3 activation and TNF expression in murine cardiomyocytes exposed to serum of septic patients or RNA.