Old Drug, New Trick: Tilorone, a Broad-Spectrum Antiviral Drug as a Potential Anti-Fibrotic Therapeutic for the Diseased Heart
Abstract
:1. Introduction
2. Results
2.1. Tilorone Attenuates Transforming Growth Factor β (TGFβ) Induced Collagen Synthesis In Vitro
2.2. Tilorone Attenuates Cardiac Fibrosis in a Mouse Model with Pre-Existing Pathological Cardiac Remodelling and Cardiac Dysfunction due to Pressure Overload
2.3. Treatment with Tilorone Is Associated with a Favourable Cardiac Stress Gene Expression Profile
2.4. Treatment with Tilorone Prevented a Further Decline in Cardiac Function
3. Discussion
4. Materials and Methods
4.1. Animal Experimental Procedures
4.2. Study Design
4.3. Pressure Overload Induced by Transverse Aortic Constriction (TAC)
4.4. Left Ventricular Structure and Function
4.5. Tissue Collection
4.6. Proline Assay
4.7. RNA Isolation
4.8. Reverse Transcription
4.9. Quantitative PCR (qPCR)
4.10. Histological Analysis
4.11. Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Sham | TAC | |||
---|---|---|---|---|
Saline | Tilorone | Saline | Tilorone | |
No. of Animals | 3 | 3 | 7 | 7 |
Body Weight (g) | 30.6 ± 0.2 | 29.5 ± 0.6 | 30.2 ± 1.0 | 31.1 ± 0.7 |
Tibial Length (mm) | 16.1 ± 0.1 | 16.1 ± 0.1 | 16.2 ± 0.1 | 16.3 ± 0.1 |
Heart Weight (mg) | 140.2 ± 13.1 | 140.0 ± 11.8 | 203.3 ± 20.6 | 199.5 ± 10.5 |
Atrial Weight (mg) | 6.4 ± 1.3 | 7.3 ± 0.5 | 14.6 ± 2.4 * | 14.3 ± 1.3 * |
Lung Weight (mg) | 162.6 ± 7.6 | 176.3 ± 7.0 | 244.5 ± 55.0 | 203.4 ± 16.8 |
HW/BW (mg/g) | 4.6 ± 0.5 | 4.7 ± 0.3 | 6.7 ± 0.7 * | 6.4 ± 0.3 |
AW/BW (mg/g) | 0.21 ± 0.05 | 0.25 ± 0.02 | 0.49 ± 0.09* | 0.46 ± 0.04 |
LW/BW (mg/g) | 5.3 ± 0.3 | 6.0 ± 0.1 | 8.3 ± 2.1 | 6.6 ± 0.6 |
HW/TL (mg/mm) | 8.7 ± 0.8 | 8.7 ± 0.8 | 12.5 ± 1.2 * | 12.3 ± 0.7 * |
AW/TL (mg/mm) | 0.40 ± 0.08 | 0.45 ± 0.03 | 0.90 ± 0.15 * | 0.88 ± 0.08 * |
LW/TL (mg/mm) | 10.1 ± 0.5 | 10.9 ± 0.5 | 15.1 ± 3.4 | 12.5 ± 1.0 |
BASELINE | 4 WEEKS POST-TAC | ENDPOINT | ||||
---|---|---|---|---|---|---|
TAC | TAC | TAC | ||||
Saline | Tilorone | Saline | Tilorone | Saline | Tilorone | |
No. of Animals | 7 | 7 | 7 | 7 | 7 | 7 |
Body Weight (g) | 29.1 ± 0.4 | 28.9 ± 0.6 | 29.8 ± 0.6 | 29.8 ± 0.5 | 30.4 ± 1.2 | 30.9 ± 0.8 |
Heart Rate (bpm) | 521 ± 16 | 559 ± 31 | 562 ± 14 | 546 ± 25 | 566 ± 22 | 574 ± 13 |
LVPW (mm) | 0.80 ± 0.01 | 0.78 ± 0.02 | 1.11 ± 0.01 * | 1.16 ± 0.01 * | 1.07 ± 0.03 * | 1.08 ± 0.02 *‡ |
IVS (mm) | 0.79 ± 0.01 | 0.79 ± 0.01 | 1.15 ± 0.01 * | 1.19 ± 0.01 * | 1.08 ± 0.03 * | 1.05 ± 0.04 *‡ |
LVEDD (mm) | 3.89 ± 0.11 | 4.04 ± 0.06 | 4.24 ± 0.08 * | 4.21 ± 0.10 | 4.32 ± 0.20 * | 4.39 ± 0.12 * |
LVESD (mm) | 2.28 ± 0.14 | 2.43 ± 0.06 | 2.96 ± 0.07 * | 2.95 ± 0.09 * | 3.31 ± 0.28 *# | 3.08 ± 0.14 * |
Fractional Shortening (%) | 42 ± 2 | 40 ± 2 | 30 ± 1 * | 30 ± 1 * | 24 ± 3 *‡ | 30 ± 1 *† |
Ejection Fraction (%) | 79 ± 2 | 78 ± 2 | 66 ± 1 * | 66 ± 1 * | 55 ± 5 *‡ | 65 ± 2 *† |
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Horlock, D.; Kaye, D.M.; Winbanks, C.E.; Gao, X.-M.; Kiriazis, H.; Donner, D.G.; Gregorevic, P.; McMullen, J.R.; Bernardo, B.C. Old Drug, New Trick: Tilorone, a Broad-Spectrum Antiviral Drug as a Potential Anti-Fibrotic Therapeutic for the Diseased Heart. Pharmaceuticals 2021, 14, 263. https://doi.org/10.3390/ph14030263
Horlock D, Kaye DM, Winbanks CE, Gao X-M, Kiriazis H, Donner DG, Gregorevic P, McMullen JR, Bernardo BC. Old Drug, New Trick: Tilorone, a Broad-Spectrum Antiviral Drug as a Potential Anti-Fibrotic Therapeutic for the Diseased Heart. Pharmaceuticals. 2021; 14(3):263. https://doi.org/10.3390/ph14030263
Chicago/Turabian StyleHorlock, Duncan, David M. Kaye, Catherine E. Winbanks, Xiao-Ming Gao, Helen Kiriazis, Daniel G. Donner, Paul Gregorevic, Julie R. McMullen, and Bianca C. Bernardo. 2021. "Old Drug, New Trick: Tilorone, a Broad-Spectrum Antiviral Drug as a Potential Anti-Fibrotic Therapeutic for the Diseased Heart" Pharmaceuticals 14, no. 3: 263. https://doi.org/10.3390/ph14030263