Title

Cardiac-Targeted Expression Of Soluble Fas Attenuates Doxorubicin-Induced Cardiotoxicity In Mice

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-α, interleukin (IL)-1β, 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. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.

Publication Date

3-1-2009

Publication Title

Journal of Pharmacology and Experimental Therapeutics

Volume

328

Issue

3

Number of Pages

740-748

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1124/jpet.108.146423

Socpus ID

62449233690 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/62449233690

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