Ribonuclease 1 attenuates septic cardiomyopathy and cardiac apoptosis in a murine model of polymicrobial sepsis
Elisabeth Zechendorf, … , Christoph Thiemermann, Lukas Martin
Elisabeth Zechendorf, … , Christoph Thiemermann, Lukas Martin
Published March 26, 2020
Citation Information: JCI Insight. 2020;5(8):e131571. https://doi.org/10.1172/jci.insight.131571.
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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 4

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.

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RNase 1 treatment or TLR3 inhibition results in decrease of caspase-3 ac...
(A) Cardiomyocytes exposed to 5 % serum of patients with sepsis (SsP) for 16 hours in presence (RNase + SsP; n = 4) or absence of 2.8 U/mL RNase 1 (n = 3) were stained with DAPI and anti-cleaved caspase-3 and compared with unstimulated cells (control; n = 3). DAPI stained the nuclei (blue) and the green immunofluorescence represents the cleaved caspase-3 (cl. caspase 3) expression. Scale bars: 50 μm. (B) Quantification of cleaved caspase-3 immunofluorescence. A 1-way ANOVA followed by Bonferroni test was used for multiple comparisons. Data are presented as dot plot with the mean ± SEM. (C) Relative TNF mRNA expression of cardiomyocytes exposed to SsP in presence of RNase 1 compared with cardiomyocytes stimulated in absence of RNase 1 (both n =3). An unpaired t test (2-tailed) was used for statistical analysis. Data are presented as dot plot with the mean ± SEM. (D) Relative caspase activity was analyzed in cardiomyocytes exposed to 100 ng/mL eRNA and unstimulated cells for 16 hours in presence (both n = 3) or absence (both n = 5) of 2 μM TLR3-Inhibitor using Caspase Glo assay. A 1-way ANOVA followed by Bonferroni test was used for multiple comparisons. Data are presented as dot plot with the mean ± SEM. §P < 0.05 versus control; #P < 0.05 versus SsP. SsP, serum of septic patients; RNase, ribonuclease 1.