Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Pharmacology and Experimental Therapeutics
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Journal of Pharmacology and Experimental Therapeutics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleTOXICOLOGY

Cardiac-Targeted Expression of Soluble Fas Attenuates Doxorubicin-Induced Cardiotoxicity in Mice

Jianli Niu, Asim Azfer, Kangkai Wang, Xihai Wang and Pappachan E. Kolattukudy
Journal of Pharmacology and Experimental Therapeutics March 2009, 328 (3) 740-748; DOI: https://doi.org/10.1124/jpet.108.146423
Jianli Niu
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Asim Azfer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kangkai Wang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xihai Wang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Pappachan E. Kolattukudy
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

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.

Footnotes

  • This work was supported by the National Institutes of Health [Grant HL69458].

  • doi:10.1124/jpet.108.146423.

  • ABBREVIATIONS: Dox, doxorubicin; FasL, Fas ligand; sFas, soluble Fas; WT, wild-type; LVEDD, left ventricular end-diastolic dimension; 3-NT, 3-nitrotyrosine; PARP, poly(ADP-ribose) polymerase; PMA, phorbol 12-myristate 13-acetate; ROS, reactive oxygen species; DHE, dihydro-β-erythroidine; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; TNF, tumor necrosis factor; IL, interleukin; iNOS, inducible NO synthase; RT, reverse transcriptase; PCR, polymerase chain reaction; NO, nitric oxide; NFAT, nuclear factor of activated T-lymphocytes; NF, nuclear factor; LV, left ventricle.

    • Received September 19, 2008.
    • Accepted December 8, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 377 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 377, Issue 2
1 May 2021
  • Table of Contents
  • About the Cover
  • Index by author
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Cardiac-Targeted Expression of Soluble Fas Attenuates Doxorubicin-Induced Cardiotoxicity in Mice
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleTOXICOLOGY

Cardiac-Targeted Expression of Soluble Fas Attenuates Doxorubicin-Induced Cardiotoxicity in Mice

Jianli Niu, Asim Azfer, Kangkai Wang, Xihai Wang and Pappachan E. Kolattukudy
Journal of Pharmacology and Experimental Therapeutics March 1, 2009, 328 (3) 740-748; DOI: https://doi.org/10.1124/jpet.108.146423

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleTOXICOLOGY

Cardiac-Targeted Expression of Soluble Fas Attenuates Doxorubicin-Induced Cardiotoxicity in Mice

Jianli Niu, Asim Azfer, Kangkai Wang, Xihai Wang and Pappachan E. Kolattukudy
Journal of Pharmacology and Experimental Therapeutics March 1, 2009, 328 (3) 740-748; DOI: https://doi.org/10.1124/jpet.108.146423
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Tolerability Profile of a GalNAc3-Conjugated ASO in Monkeys
  • Preclinical Safety of Lung Instillation of Thyroid Hormone
  • Nefazodone Inhibits Anaerobic Glycolysis
Show more Toxicology

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics