Ribonuclease 1 attenuates septic cardiomyopathy and cardiac apoptosis in a murine model of polymicrobial 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
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
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Research Article Immunology Inflammation

Ribonuclease 1 attenuates septic cardiomyopathy and cardiac apoptosis in a murine model of polymicrobial sepsis

Abstract

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.

Authors

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

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Figure 7

RNase 1 treatment of mice with polymicrobial sepsis resulted in a decreased TNF expression.

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RNase 1 treatment of mice with polymicrobial sepsis resulted in a decrea...
(A) TNF, (B) RNase 1 and (C) RNH1 serum levels of sham-operated mice treated with vehicle (n = 11) or RNase 1 (n = 5) or mice with polymicrobial sepsis induced by CLP treated with vehicle (n = 8) or RNase 1 (n = 9) were analyzed by ELISA. An unpaired t test (2-tailed) was used for statistical analysis (A and C). In B, a 1-way ANOVA followed by Bonferroni test was used for multiple comparisons. Data are presented as dot plot with the mean ± SEM. (D) Total extracellular RNA in serum of mice are demonstrated. A 1-way ANOVA followed by Bonferroni test was used for multiple comparisons. Data are presented as dot plot with the mean ± SEM. (E) RNase 1 serum levels over the time in sham-operated mice (n = 3) and mice with polymicrobial sepsis induced by CLP treated with vehicle (n = 4). Correlation of TNF and RNase 1 of mice with polymicrobial sepsis induced by CLP (F) treated with vehicle and (G) treated with RNase 1. §P < 0.05 versus sham; #P < 0.05 versus CLP + vehicle. CLP, cecal ligation and puncture; RNase, ribonuclease 1; RNH1, ribonuclease-inhibitor 1.