AHA Journals – Circulation Research: Abstract 456: Early Doxorubicin Exposure Upregulates P-STAT3 Expression in Adult Murine Model

Background: Anthracyclines such as doxorubicin (DOX) is a key component of chemotherapy treatments and also have cardiotoxic effects that can manifest decades after initial exposure. Long term survivors have a 15 times greater risk of heart failure than the general population. Previously, our lab has shown an increase in serum leptin in DOX treated animals 15 months after exposure. Altered p-STAT3 activation has been shown in inpatient and mouse models of heart failure and is downstream of leptin receptor activation. Our overall aim was to evaluate p- STAT3 levels in mice hearts of aged mice previously exposed to doxorubicin during development.

Methods: C57/BL6J mice were injected weekly intraperitoneally with saline or 1 mg/kg, 3 mg/kg/ and 5mg/kg/ week of the DOX from 2 weeks to 6 weeks of age. At 7 weeks one cohort of mice was harvested. At 15 months a second cohort was harvested. Hearts were cut in half and one-half paraffin sectioned. From the other half, heart lysates were prepared. P-STAT3 and STAT3 expression was evaluated by Immunohistochemistry and Western blots.

Results and Conclusions: Western blot confirms a dose-dependent upregulation of p-STAT3 expression in DOX treated mice hearts at 80 weeks old compared to controls (1.13 VS. 0.04, p-STAT3/STAT3 ratio). In addition, p-STAT3 is increased by immunohistochemistry. This indicates that early exposure to DOX may produce changes in the heart that continue throughout life. These findings suggest that gene targets of activated p-STAT3 may drive the gradual progression to heart failure in patients exposed to anthracyclines during childhood. Future studies may elucidate therapeutic targets to slow the progression of heart failure in these patients.