Ribonuclease 1 Attenuates Septic Cardiomyopathy and Cardiac Apoptosis in a Murine Model of Polymicrobial Sepsis

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2020 Mar 28

PMID 32213712

Citations 24

Authors

Elisabeth Zechendorf

Caroline E ORiordan

Lara Stiehler

Natalie Wischmeyer

Fausto Chiazza

Debora Collotta

Bernd Denecke

Sabrina Ernst

Gerhard Muller-Newen

Sina M Coldewey

Bianka Wissuwa

Massimo Collino

Tim-Philipp Simon

Tobias Schuerholz

Christian Stoppe

Gernot Marx

Christoph Thiemermann

Lukas Martin

Affiliations

Soon will be listed here.

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.

Citing Articles

Exceptional Uptake, Limited Protein Expression: Liver Macrophages Lost in Translation of Synthetic mRNA.

Lin C, Kuzmanovic A, Wang N, Liao L, Ernst S, Penners C Adv Sci (Weinh). 2025; 12(9):e2409729.

PMID: 39792811 PMC: 11884593. DOI: 10.1002/advs.202409729.

Acetylation of TIR domains in the TLR4-Mal-MyD88 complex regulates immune responses in sepsis.

Li X, Li X, Huang P, Zhang F, Du J, Kong Y EMBO J. 2024; 43(21):4954-4983.

PMID: 39294473 PMC: 11535217. DOI: 10.1038/s44318-024-00237-8.

Ribonuclease inhibitor 1 emerges as a potential biomarker and modulates inflammation and iron homeostasis in sepsis.

Neu C, Beckers C, Frank N, Thomas K, Bartneck M, Simon T Sci Rep. 2024; 14(1):14972.

PMID: 38951571 PMC: 11217267. DOI: 10.1038/s41598-024-65778-8.

New link between RNH1 and E2F1: regulates the development of lung adenocarcinoma.

Zhao W, Liu Y, Yang Y, Wang L BMC Cancer. 2024; 24(1):635.

PMID: 38783241 PMC: 11118993. DOI: 10.1186/s12885-024-12392-6.

[Spermidine alleviates lipopolysaccharide-induced myocardial injury in mice by suppressing apoptosis, ROS production and ferroptosis].

Zhang X, Zhao P, Kuai J, Chang C, Yuan Q Nan Fang Yi Ke Da Xue Xue Bao. 2024; 44(1):166-172.

PMID: 38293988 PMC: 10878897. DOI: 10.12122/j.issn.1673-4254.2024.01.19.

References

Zechendorf E, Vassen P, Zhang J, Hallawa A, Martincuks A, Krenkel O . Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical- Approach Combining Experiments and Machine Learning. Front Immunol. 2018; 9:393. PMC: 5869260. DOI: 10.3389/fimmu.2018.00393. View

Gould T, Vu T, Stafford A, Dwivedi D, Kim P, Fox-Robichaud A . Cell-Free DNA Modulates Clot Structure and Impairs Fibrinolysis in Sepsis. Arterioscler Thromb Vasc Biol. 2015; 35(12):2544-53. DOI: 10.1161/ATVBAHA.115.306035. View

Lomax J, Bianchetti C, Chang A, Phillips Jr G, Fox B, Raines R . Functional evolution of ribonuclease inhibitor: insights from birds and reptiles. J Mol Biol. 2014; 426(17):3041-56. PMC: 4219644. DOI: 10.1016/j.jmb.2014.06.007. View

Feng Y, Chen H, Cai J, Zou L, Yan D, Xu G . Cardiac RNA induces inflammatory responses in cardiomyocytes and immune cells via Toll-like receptor 7 signaling. J Biol Chem. 2015; 290(44):26688-98. PMC: 4646323. DOI: 10.1074/jbc.M115.661835. View

Cabrera-Fuentes H, Ruiz-Meana M, Simsekyilmaz S, Kostin S, Inserte J, Saffarzadeh M . RNase1 prevents the damaging interplay between extracellular RNA and tumour necrosis factor-α in cardiac ischaemia/reperfusion injury. Thromb Haemost. 2014; 112(6):1110-9. DOI: 10.1160/TH14-08-0703. View

Coldewey S, Benetti E, Collino M, Pfeilschifter J, Sponholz C, Bauer M . Elevation of serum sphingosine-1-phosphate attenuates impaired cardiac function in experimental sepsis. Sci Rep. 2016; 6:27594. PMC: 4899780. DOI: 10.1038/srep27594. View

Martin L, Peters C, Schmitz S, Moellmann J, Martincuks A, Heussen N . Soluble Heparan Sulfate in Serum of Septic Shock Patients Induces Mitochondrial Dysfunction in Murine Cardiomyocytes. Shock. 2015; 44(6):569-77. DOI: 10.1097/SHK.0000000000000462. View

Martin L, Derwall M, Al Zoubi S, Zechendorf E, Reuter D, Thiemermann C . The Septic Heart: Current Understanding of Molecular Mechanisms and Clinical Implications. Chest. 2018; 155(2):427-437. DOI: 10.1016/j.chest.2018.08.1037. View

Martin L, Koczera P, Simons N, Zechendorf E, Hoeger J, Marx G . The Human Host Defense Ribonucleases 1, 3 and 7 Are Elevated in Patients with Sepsis after Major Surgery--A Pilot Study. Int J Mol Sci. 2016; 17(3):294. PMC: 4813158. DOI: 10.3390/ijms17030294. View

10.

Martin L, Schmitz S, De Santis R, Doemming S, Haase H, Hoeger J . Peptide 19-2.5 inhibits heparan sulfate-triggered inflammation in murine cardiomyocytes stimulated with human sepsis serum. PLoS One. 2015; 10(5):e0127584. PMC: 4449035. DOI: 10.1371/journal.pone.0127584. View

11.

Schneck E, Samara O, Koch C, Hecker A, Padberg W, Lichtenstern C . Plasma DNA and RNA differentially impact coagulation during abdominal sepsis-an explorative study. J Surg Res. 2017; 210:231-243. DOI: 10.1016/j.jss.2016.11.044. View

12.

Laugwitz K, Moretti A, Weig H, Gillitzer A, Pinkernell K, Ott T . Blocking caspase-activated apoptosis improves contractility in failing myocardium. Hum Gene Ther. 2001; 12(17):2051-63. DOI: 10.1089/10430340152677403. View

13.

. Incidence of severe sepsis and septic shock in German intensive care units: the prospective, multicentre INSEP study. Intensive Care Med. 2016; 42(12):1980-1989. DOI: 10.1007/s00134-016-4504-3. View

14.

Kannemeier C, Shibamiya A, Nakazawa F, Trusheim H, Ruppert C, Markart P . Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci U S A. 2007; 104(15):6388-93. PMC: 1851071. DOI: 10.1073/pnas.0608647104. View

15.

Sordi R, Chiazza F, Johnson F, Patel N, Brohi K, Collino M . Inhibition of IκB Kinase Attenuates the Organ Injury and Dysfunction Associated with Hemorrhagic Shock. Mol Med. 2015; 21:563-75. PMC: 4607620. DOI: 10.2119/molmed.2015.00049. View

16.

Singer M, Deutschman C, Seymour C, Shankar-Hari M, Annane D, Bauer M . The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315(8):801-10. PMC: 4968574. DOI: 10.1001/jama.2016.0287. View

17.

Chan J, Roth J, Oppenheim J, Tracey K, Vogl T, Feldmann M . Alarmins: awaiting a clinical response. J Clin Invest. 2012; 122(8):2711-9. PMC: 3408740. DOI: 10.1172/JCI62423. View

18.

Kim N, Kang P . Apoptosis in cardiovascular diseases: mechanism and clinical implications. Korean Circ J. 2010; 40(7):299-305. PMC: 2910284. DOI: 10.4070/kcj.2010.40.7.299. View

19.

Sato R, Kuriyama A, Takada T, Nasu M, Luthe S . Prevalence and risk factors of sepsis-induced cardiomyopathy: A retrospective cohort study. Medicine (Baltimore). 2016; 95(39):e5031. PMC: 5265970. DOI: 10.1097/MD.0000000000005031. View

20.

Martin L, Koczera P, Zechendorf E, Schuerholz T . The Endothelial Glycocalyx: New Diagnostic and Therapeutic Approaches in Sepsis. Biomed Res Int. 2016; 2016:3758278. PMC: 5028820. DOI: 10.1155/2016/3758278. View