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Updated: Jun 10, 2026
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Modulation of doxorubicin-induced cardiac dysfunction in dominant-negative p38α mitogen-activated protein kinase mice
Rajarajan A Thandavarayan1, Kenichi Watanabe, Flori R Sari
1Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata City 956-8603, Japan.
Abstract:
Doxorubicin (Dox) is a widely used antitumor drug, but its application is limited because of its cardiotoxic side effects. Increased expression of p38α mitogen-activated protein kinase (MAPK) promotes cardiomyocyte apoptosis and is associated with cardiac dysfunction induced by prolonged agonist stimulation. However, the role of p38α MAPK is not clear in Dox-induced cardiac injury. Cardiac dysfunction was induced by a single injection of Dox into wild-type (WT) mice and transgenic mice with cardiac-specific expression of a dominant-negative mutant form of p38α MAPK (TG). Left ventricular (LV) fractional shortening and ejection fraction were higher and the expression levels of phospho-p38 MAPK and phospho-MAPK-activated mitogen kinase 2 were significantly suppressed in TG mouse heart compared to WT mice after Dox injection. Production of LV proinflammatory cytokines, cardiomyocyte DNA damage, myocardial apoptosis, caspase-3-positive cells, and phospho-p53 expression were decreased in TG mice after Dox injection. Moreover, LV expression of NADPH oxidase subunits and reactive oxygen species was significantly less in TG mice compared to WT mice after Dox injection. These findings suggest that p38α MAPK may play a role in the regulation of cardiac function, oxidative stress, and inflammatory and apoptotic mediators in the heart after Dox administration.
Insights
p38α MAPK inhibition protects against Doxorubicin-induced cardiotoxicity by reducing inflammation and apoptosis. This study highlights p38α MAPK as a potential therapeutic target for mitigating Doxorubicin
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Pharmacology
Background:
- Doxorubicin (Dox) is a vital anticancer drug, yet its clinical use is hampered by cardiotoxicity.
- p38α mitogen-activated protein kinase (MAPK) is implicated in cardiomyocyte apoptosis and cardiac dysfunction, but its specific role in Dox-induced injury remains unclear.
Purpose of the Study:
- To investigate the role of p38α MAPK in Doxorubicin-induced cardiotoxicity.
- To evaluate the protective effects of inhibiting p38α MAPK against Doxorubicin-induced cardiac damage.
Main Methods:
- Cardiac dysfunction was induced in wild-type (WT) and transgenic (TG) mice with cardiac-specific dominant-negative p38α MAPK expression via a single Dox injection.
- Evaluated left ventricular (LV) function, inflammatory markers, DNA damage, apoptosis, and oxidative stress.
Main Results:
- TG mice exhibited preserved LV function (fractional shortening, ejection fraction) compared to WT mice post-Dox.
- Dox-induced increases in phospho-p38 MAPK, proinflammatory cytokines, DNA damage, apoptosis, and oxidative stress markers were significantly reduced in TG mice.
- Expression of NADPH oxidase subunits and reactive oxygen species was lower in TG mice.
Conclusions:
- p38α MAPK plays a critical role in mediating Doxorubicin-induced cardiotoxicity.
- Inhibition of p38α MAPK confers protection against Doxorubicin-induced cardiac injury by suppressing inflammation, apoptosis, and oxidative stress.
- Targeting p38α MAPK may represent a viable strategy to prevent or treat Doxorubicin cardiotoxicity.
