ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage
Abstract
:1. Introduction
2. Results
2.1. Influence of ONX 0914 on Myocarditis in NMRI Mice
2.2. Influence of ONX 0914 on the Molecular Architecture of the 20S Proteasome Complex in Viral Myocarditis
3. Discussion
4. Materials and Methods
4.1. Mouse Studies
4.2. Echocardiography
4.3. Proteasome Inhibitor ONX 0914
4.4. Quantification of Infectious Viral Particles
4.5. Histology
4.6. Flow Cytometry
4.7. RNA Isolation, cDNA Synthesis, and qPCR
4.8. Western Blot Analysis
4.9. Statistics
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
bpm | beats per minute |
CCL2 | chemokine ligand 2 |
CCL4 | chemokine ligand 4 |
CVB3 | coxsackievirus B3 |
CXCL2 | C-X-C- motif chemokine ligand 2 |
CXCL10 | C-X-C- motif chemokine ligand 10 |
DAMP | damage-associated molecular pattern |
EF | ejection fraction |
HE | hematoxylin-eosin |
IL | interleukin |
IFIT1/3 | interferon-induced protein with tetratricopeptide repeats 1/3 |
IFN | interferon |
i-proteasome | immunoproteasome |
LMP2 | low molecular weight protein 2 |
LMP7 | low molecular weight protein 7 |
LVID-d/-s | left ventricular inner dimension at diastole/systole |
LCMV | lymphocytic choriomeningitis virus |
MHC | major histocompatibility complex |
mHPRT | mouse hypoxanthine-guanine phosphoribosyl transferase |
MECL-1 | multicatalytic endopeptidase complex-like 1 |
PAMP | pathogen-associated molecular pattern |
PW-Doppler | pulsed-wave Doppler |
(hs)TnT | (high sensitive) troponin T |
UPS | ubiquitin-proteasome system |
vol d/s | end-diastolic/end-systolic volume |
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Collumn Name | Vehicle | ONX 0914 | ||
---|---|---|---|---|
Baseline | Day 28 | Baseline | Day 28 | |
Heart rate (bpm) | 417 ± 18 | 440 ± 18 | 440 ± 18 | 426 ± 14 |
Trace EF (%) | 46 ± 2.5 | 48.1 ± 2.9 | 43.6 ± 2.6 | 42.7 ± 2.0 |
Cardiac output (mL/min) | 13.6 ± 1.0 | 14.6 ± 1.0 | 14.3 ± 1.1 | 14.0 ± 0.8 |
Stroke volume (µL) | 32.4 ± 1.8 | 32.7 ± 1.5 | 32.0 ± 1.9 | 33.0 ± 1.8 |
Vol d (µL) | 70.5 ± 1.7 | 70.0 ± 3.1 | 74.2 ± 3 | 77.0 ± 2.2 |
Vol s (µL) | 38.1 ± 1.9 | 37.3 ± 3.0 | 42.2 ± 2.9 | 44.2 ± 2.0 |
LVID-d (mm) | 4.3 ± 0.1 | 4.3 ± 0.1 | 4.3 ± 0.1 | 4.5 ± 0.1 |
LVID-s (mm) | 3.2 ± 0.1 | 3.1 ± 0.1 | 3.2 ± 0.1 | 3.5 ± 0.1 |
Vehicle | ONX 0914 | |||
---|---|---|---|---|
Baseline | Day 8 | Baseline | Day 8 | |
Heart rate (bpm) | 427 ± 16 | 393 ± 16 | 500 ± 13 * | 405 ± 23 § |
Trace EF (%) | 50.7 ± 1.7 | 48.4 ± 2.6 | 57.4 ± 2.3 | 49.1 ± 3.2 § |
Cardiac output (mL/min) | 14.4 ± 1.2 | 10.0 ± 0.9 § | 18.6 ± 1.2 * | 12.1 ± 1.3 § |
Stroke volume (µL) | 33.6 ± 2.1 | 25.2 ± 1.4 § | 37.3 ± 2.4 | 29.6 ± 2.3 § |
Vol d (µL) | 66.5 ± 4.0 | 52.8 ± 3.0 § | 65.5 ± 4.0 | 60.3 ± 2.6 |
Vol s (µL) | 33.0 ± 2.4 | 27.6 ± 2.6 | 28.1 ± 2.5 | 30.7 ± 2.3 |
LVID-d (mm) | 4.2 ± 0.1 | 4.0 ± 0.1 | 4.2 ± 0.1 | 4.2 ± 0.1 |
LVID-s (mm) | 3.1 ± 0.1 | 3.0 ± 0.1 | 2.9 ± 0.1 | 3.2 ± 0.1 |
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Neumaier, H.L.; Harel, S.; Klingel, K.; Kaya, Z.; Heuser, A.; Kespohl, M.; Beling, A. ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage. Cells 2020, 9, 1093. https://doi.org/10.3390/cells9051093
Neumaier HL, Harel S, Klingel K, Kaya Z, Heuser A, Kespohl M, Beling A. ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage. Cells. 2020; 9(5):1093. https://doi.org/10.3390/cells9051093
Chicago/Turabian StyleNeumaier, Hannah Louise, Shelly Harel, Karin Klingel, Ziya Kaya, Arnd Heuser, Meike Kespohl, and Antje Beling. 2020. "ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage" Cells 9, no. 5: 1093. https://doi.org/10.3390/cells9051093
APA StyleNeumaier, H. L., Harel, S., Klingel, K., Kaya, Z., Heuser, A., Kespohl, M., & Beling, A. (2020). ONX 0914 Lacks Selectivity for the Cardiac Immunoproteasome in CoxsackievirusB3 Myocarditis of NMRI Mice and Promotes Virus-Mediated Tissue Damage. Cells, 9(5), 1093. https://doi.org/10.3390/cells9051093