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Updated: Jun 27, 2026
A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
Published on: May 16, 2020
Cardiac-targeted expression of soluble fas attenuates doxorubicin-induced cardiotoxicity in mice
Jianli Niu1, Asim Azfer, Kangkai Wang
1Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Bldg. 20, Room 125, Orlando, FL 32826-2364, USA. jniu@mail.ucf.edu
Abstract:
Doxorubicin (Dox) is known to cause cardiomyopathy and congestive heart failure upon chronic administration. The mechanisms underlying these toxicities remain uncertain but have been attributed, at least in part, by induction of cardiac cell apoptosis. Fas ligation with its cognate ligand (FasL) induces apoptosis and activates cellular inflammatory responses associated with tissue injury. We determined whether interruption of Fas/FasL interaction by cardiac-targeted expression of soluble Fas (sFas), a competitive inhibitor of FasL, would protect against Dox chronic cardiotoxicity in mice. Wild-type (WT) and sFas transgenic mice were administrated intravenously with 4 mg/kg Dox or with an equivalent volume of saline twice a week for a total of 10 injections. There were 25% mortality in WT mice, but no death was observed in sFas mice during the period of Dox treatment. Echocardiographic evaluation revealed a significant decrease in left ventricle fractional shortening after Dox treatment in WT mice but not in sFas mice. WT mice treated with Dox developed extensive myocardial cytoplasmic vacuolization, apoptosis, and interstitial fibrosis, which were much less or absent in sFas mice. The increased inducible nitric oxide synthase expression, nitric oxide production, superoxide generation, and peroxynitrite formation after Dox treatment in WT mice were attenuated by sFas expression. sFas expression also attenuated Dox-mediated induction of proinflammatory cytokines, tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 in the myocardium. These observations indicate that FasL is an important mediator in Dox-associated cardiotoxicity by generating reactive oxygen and nitrogen species.
Insights
Doxorubicin (Dox) causes heart damage by inducing apoptosis. Blocking the Fas/FasL pathway with soluble Fas (sFas) significantly protected mice from Dox-induced cardiotoxicity, reducing mortality and preserving heart function.
Area of Science:
- Cardiology
- Toxicology
- Molecular Biology
Background:
- Doxorubicin (Dox) is a widely used chemotherapy agent.
- Chronic Dox administration is associated with cardiotoxicity, leading to cardiomyopathy and heart failure.
- The precise mechanisms of Dox-induced cardiotoxicity are not fully understood but involve cardiac cell apoptosis.
Purpose of the Study:
- To investigate the role of the Fas/FasL pathway in Doxorubicin-induced cardiotoxicity.
- To determine if inhibiting Fas/FasL interaction with cardiac-targeted soluble Fas (sFas) can protect against Dox-induced heart damage.
Main Methods:
- Wild-type (WT) and sFas transgenic mice received intravenous Dox (4 mg/kg) or saline twice weekly for 10 injections.
- Mortality, echocardiographic parameters (left ventricle fractional shortening), and myocardial histology were assessed.
- Levels of inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), reactive nitrogen species (RNS), and proinflammatory cytokines were measured.
Main Results:
- Dox treatment resulted in 25% mortality in WT mice, whereas no deaths occurred in sFas mice.
- WT mice showed significant decreases in left ventricle fractional shortening, myocardial vacuolization, apoptosis, and fibrosis after Dox, which were attenuated in sFas mice.
- sFas expression reduced Dox-induced increases in iNOS, nitric oxide, superoxide, peroxynitrite, and proinflammatory cytokines (TNF-α, IL-1β, IL-6).
Conclusions:
- FasL is a key mediator in Doxorubicin-induced cardiotoxicity.
- Inhibition of Fas/FasL interaction via sFas provides significant protection against Dox cardiotoxicity.
- The protective effects are associated with reduced oxidative and nitrosative stress and attenuated inflammatory responses in the myocardium.
