Transcriptional analysis of doxorubicin-induced cardiotoxicity.

Abstract

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.

• Authors: Xiaoming Yi, Raffi Bekeredjian, Nicholas J DeFilippis, Zakir Siddiquee, Eduardo Fernandez, Ralph V Shohet
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 290 Issue 3 Pg. H1098-102 (Mar 2006) ISSN: 0363-6135 [Print] United States
• PMID: 16243910 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Transcription Factors
• Doxorubicin

Topics

• Animals
• Cardiomyopathy, Dilated (chemically induced, metabolism, pathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Doxorubicin (administration & dosage, toxicity)
• Heart (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardium (metabolism)
• Transcription Factors (metabolism)
• Ventricular Dysfunction, Left (chemically induced, metabolism, pathology)