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Updated: Apr 15, 2026
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Acute doxorubicin-induced cardiotoxicity is associated with matrix metalloproteinase-2 alterations in rats
Bertha Furlan Polegato1, Marcos Ferreira Minicucci, Paula Schmidt Azevedo
1Internal Medicine Department, Botucatu Medical School, Univ Estadual Paulista (UNESP), Brazil.
Background:
Doxorubicin can cause cardiotoxicity. Matrix metalloproteinases (MMP) are responsible for degrading extracellular matrix components which play a role in ventricular dilation. Increased MMP activity occurs after chronic doxorubicin treatment. In this study we evaluated in vivo and in vitro cardiac function in rats with acute doxorubicin treatment, and examined myocardial MMP and inflammatory activation, and gene expression of proteins involved in myocyte calcium transients.
Methods:
Wistar rats were injected with doxorubicin (Doxo, 20 mg/kg) or saline (Control). Echocardiogram was performed 48 h after treatment. Myocardial function was assessed in vitro in Langendorff preparation.
Results:
In left ventricle, doxorubicin impaired fractional shortening (Control 0.59 ± 0.07; Doxo 0.51 ± 0.05; p < 0.001), and increased isovolumetric relaxation time (Control 20.3 ± 4.3; Doxo 24.7 ± 4.2 ms; p = 0.007) and myocardial passive stiffness. MMP-2 activity, evaluated by zymography, was increased in Doxo (Control 141338 ± 8924; Doxo 188874 ± 7652 arbitrary units; p < 0.001). There were no changes in TNF-α, INF-γ, IL-10, and ICAM-1 myocardial levels. Expression of phospholamban, Serca-2a, and ryanodine receptor did not differ between groups.
Conclusion:
Acute doxorubicin administration induces in vivo left ventricular dysfunction and in vitro increased myocardial passive stiffness in rats. Cardiac dysfunction is related to myocardial MMP-2 activation. Increased inflammatory stimulation or changed expression of the proteins involved in intracellular calcium transients is not involved in acute cardiac dysfunction.
Insights
Acute doxorubicin treatment impairs heart function in rats by increasing matrix metalloproteinase-2 (MMP-2) activity. This study reveals MMP-2 activation as a key factor in doxorubicin-induced cardiac dysfunction.
Area of Science:
- Cardiology
- Pharmacology
- Biochemistry
Background:
- Doxorubicin (Doxo) is a potent chemotherapy agent known to induce cardiotoxicity.
- Matrix metalloproteinases (MMPs) degrade extracellular matrix and are implicated in ventricular remodeling.
- Increased MMP activity is observed following chronic Doxo exposure, suggesting a role in cardiac dysfunction.
Purpose of the Study:
- To investigate the effects of acute doxorubicin administration on cardiac function in rats.
- To examine myocardial matrix metalloproteinase (MMP) activation and inflammatory responses.
- To assess the gene expression of proteins involved in myocyte calcium handling.
Main Methods:
- Wistar rats received acute doxorubicin (20 mg/kg) or saline (Control) injection.
- Echocardiography assessed in vivo cardiac function 48 hours post-treatment.
- In vitro myocardial function was evaluated using Langendorff preparations.
Main Results:
- Doxorubicin significantly impaired left ventricular fractional shortening and increased isovolumetric relaxation time.
- Myocardial passive stiffness was elevated in the doxorubicin-treated group.
- MMP-2 activity, assessed by zymography, was significantly increased post-doxorubicin treatment.
Conclusions:
- Acute doxorubicin administration induces left ventricular dysfunction and myocardial stiffness in rats.
- Cardiac dysfunction is directly linked to increased myocardial MMP-2 activation.
- Acute doxorubicin-induced cardiac dysfunction is not associated with inflammatory stimulation or altered expression of key calcium-handling proteins.
