This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 119/1/99    most recent CIRCULATIONAHA.108.799700v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhu, W. Articles by Field, L. J. Search for Related Content PubMed PubMed Citation Articles by Zhu, W. Articles by Field, L. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB DOXORUBICIN Medline Plus Health Information Heart Diseases Related Collections Animal models of human disease Apoptosis Cell signalling/signal transduction Genetically altered mice Related Article

(Circulation. 2009;119:99-106.)
© 2009 American Heart Association, Inc.

Molecular Cardiology

Acute Doxorubicin Cardiotoxicity Is Associated With p53-Induced Inhibition of the Mammalian Target of Rapamycin Pathway

Wuqiang Zhu, MD, PhD; Mark H. Soonpaa, PhD; Hanying Chen, MD; Weihua Shen, PhD; R. Mark Payne, MD; Edward A. Liechty, MD; Randall L. Caldwell, MD; Weinian Shou, PhD; Loren J. Field, PhD

From the Riley Heart Research Center, Herman B. Wells Center for Pediatric Research (W.Z., M.H.S., H.C., W.S., R.M.P., E.A.L., R.L.C., W.S., L.J.F.), and the Krannert Institute of Cardiology (L.J.F.), Indiana University School of Medicine, Indianapolis, Ind.

Correspondence to Loren Field, Wells Center, 1044 W Walnut St, R4 Bldg, Room W376, Indianapolis, IN 46202-5225. E-mail ljfield{at}iupui.edu

Received June 16, 2008; accepted October 17, 2008.

Background— Doxorubicin is used to treat childhood and adult cancer. Doxorubicin treatment is associated with both acute and chronic cardiotoxicity. The cardiotoxic effects of doxorubicin are cumulative, which limits its chemotherapeutic dose. Free radical generation and p53-dependent apoptosis are thought to contribute to doxorubicin-induced cardiotoxicity.

Methods and Results— Adult transgenic (MHC-CB7) mice expressing cardiomyocyte-restricted dominant-interfering p53 and their nontransgenic littermates were treated with doxorubicin (20 mg/kg cumulative dose). Nontransgenic mice exhibited reduced left ventricular systolic function (predoxorubicin fractional shortening [FS] 61±2%, postdoxorubicin FS 45±2%, mean±SEM, P<0.008), reduced cardiac mass, and high levels of cardiomyocyte apoptosis 7 days after the initiation of doxorubicin treatment. In contrast, doxorubicin-treated MHC-CB7 mice exhibited normal left ventricular systolic function (predoxorubicin FS 63±2%, postdoxorubicin FS 60±2%, P>0.008), normal cardiac mass, and low levels of cardiomyocyte apoptosis. Western blot analyses indicated that mTOR (mammalian target of rapamycin) signaling was inhibited in doxorubicin-treated nontransgenic mice but not in doxorubicin-treated MHC-CB7 mice. Accordingly, transgenic mice with cardiomyocyte-restricted, constitutively active mTOR expression (MHC-mTORca) were studied. Left ventricular systolic function (predoxorubicin FS 64±2%, postdoxorubicin FS 60±3%, P>0.008) and cardiac mass were normal in doxorubicin-treated MHC-mTORca mice, despite levels of cardiomyocyte apoptosis similar to those seen in doxorubicin-treated nontransgenic mice.

Conclusions— These data suggest that doxorubicin treatment induces acute cardiac dysfunction and reduces cardiac mass via p53-dependent inhibition of mTOR signaling and that loss of myocardial mass, and not cardiomyocyte apoptosis, is the major contributor to acute doxorubicin cardiotoxicity.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2009 119: 1-4. [Extract] [Full Text]