Transcriptional analysis of doxorubicin-induced cardiotoxicity.
Doxorubicin is an effective chemotherapeutic agent against a broad range of tumors. However, a threshold dose of doxorubicin causes an unacceptably high incidence of heart failure and limits its clinical utility. We have established two models of doxorubicin cardiotoxicity in mice: 1) in an acute model, mice are treated with 15 mg/kg of doxorubicin once; and 2) in a chronic model, they receive 3 mg/kg weekly for 12 wk. Using echocardiography, we have monitored left ventricular function during treatment in the chronic model and seen the expected development of dilated cardiomyopathy. Treated mice showed histological abnormalities similar to those seen in patients with doxorubicin cardiomyopathy. To investigate transcriptional regulation in these models, we used a muscle-specific cDNA microarray. We have identified genes that respond to doxorubicin exposure in both models and confirmed these results using real-time PCR. In the acute model, a set of genes is regulated early and rapidly returns to baseline levels, consistent with the half-life of doxorubicin. In the chronic model, which mimics the clinical situation much more closely, we identified dysregulated genes that implicate specific mechanisms of cardiac toxicity. These include STARS, a hypertrophy-responsive gene; SNF1-kinase, a potential modulator of ATP levels; and AXUD1, a downstream target of the proapoptotic regulator AXIN1.
Yi
Xiaoming
X
Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center at Dallas, USA.
Bekeredjian
Raffi
R
DeFilippis
Nicholas J
NJ
Siddiquee
Zakir
Z
Fernandez
Eduardo
E
Shohet
Ralph V
RV
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D006321:Heart / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology
D014157:Transcription Factors; D004317:Doxorubicin