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Updated: May 17, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Matrix metalloproteinase inhibition protects against junctophilin-2 proteolysis during doxorubicin-induced
Wesam Bassiouni1,2, Brandon Y H Chan1,3, Andrej Roczkowsky1
1Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Background And Purpose:
Treatment of cancer patients with anthracyclines is known to cause dose-dependent cardiotoxicity through several mechanisms including enhanced oxidative stress, ultimately resulting in defective excitation-contraction coupling. Loss of junctophilin-2 (JPH-2), which tethers transverse tubules (T-tubules) to the sarcoplasmic reticulum, is a feature of doxorubicin-induced cardiotoxicity, yet the protease involved in unclear. As activation of matrix metalloproteinase-2 (MMP-2) is known to contribute to doxorubicin-induced cardiotoxicity, we investigated here the role of MMP-2 in JPH-2 proteolysis and defective calcium transients in it.
Experimental Approach:
C57BL/6J mice were treated with doxorubicin for 4 weeks with or without the MMP inhibitor (doxycycline), MMP-2 preferring inhibitor (ONO-4817) or vehicle, and cardiac function was assessed using echocardiography. JPH-2 levels in ventricular extracts were measured. Calcium transients and JPH-2 levels were measured in neonatal rat ventricular cardiomyocytes treated with doxorubicin and ONO-4817.
Key Results:
Both MMP inhibitors attenuated doxorubicin-induced cardiac systolic and diastolic dysfunction. Doxorubicin treatment resulted in JPH-2 cleavage in mouse hearts as evidenced by the appearance of lower molecular weight products of 63 and 25 kDa, which was prevented by MMP inhibitors. Loss of JPH-2 and impaired calcium transients were observed in neonatal rat ventricular cardiomyocytes treated with doxorubicin, while ONO-4817 attenuated these changes. In silico analysis predicted cleavage sites between JPH-2 MORN repeats and within its unstructured region.
Conclusions And Implications:
These results reveal that JPH-2 proteolysis is a consequence of MMP-2 activation and highlight the beneficial prophylactic action of two orally available MMP inhibitors in preventing doxorubicin-induced cardiotoxicity.
Insights
Matrix metalloproteinase-2 (MMP-2) activation causes junctophilin-2 (JPH-2) proteolysis, leading to doxorubicin-induced cardiotoxicity. MMP-2 inhibitors offer a promising prophylactic strategy against this heart damage.
Area of Science:
- Cardiology
- Molecular Biology
- Pharmacology
Background:
- Anthracyclines, like doxorubicin, cause dose-dependent cardiotoxicity.
- This cardiotoxicity involves oxidative stress and defective excitation-contraction coupling.
- Loss of junctophilin-2 (JPH-2) is observed, but the responsible protease is unknown.
Purpose of the Study:
- To investigate the role of matrix metalloproteinase-2 (MMP-2) in JPH-2 proteolysis.
- To determine if MMP-2 inhibition can prevent doxorubicin-induced cardiotoxicity.
Main Methods:
- Mice treated with doxorubicin and MMP inhibitors (doxycycline, ONO-4817) or vehicle.
- Cardiac function assessed via echocardiography.
- JPH-2 levels and calcium transients measured in cardiomyocytes.
Main Results:
- MMP inhibitors attenuated doxorubicin-induced cardiac dysfunction.
- Doxorubicin treatment led to JPH-2 cleavage, prevented by MMP inhibitors.
- JPH-2 loss and impaired calcium transients in cardiomyocytes were reversed by ONO-4817.
Conclusions:
- JPH-2 proteolysis is a result of MMP-2 activation.
- MMP-2 inhibitors demonstrate prophylactic benefits against doxorubicin cardiotoxicity.
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