Abstract 4489: Angiotensin-(1-7) prevents fibrosis in doxorubicin-treated rats

Abstract

Abstract Anthracyclines such as doxorubicin (Dox) are effective chemotherapeutic agents for multiple malignancies, including childhood leukemias and sarcomas. Despite the efficacy of these agents, anthracyclines can result in cumulative dose-dependent cardiac toxicity that manifests as cardiomyopathy with marked myocardial hypertrophy and fibrosis. This cardiotoxicity culminates in reduced ejection fraction, fractional shortening, and cardiac output, leading to congestive heart failure. Consequently, there is an unmet need for adjunct therapies to temper anthracycline-induced cardiotoxicity and enhance long-term quality of life in patients treated with anthracyclines, especially pediatric cancer patients. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous seven amino acid peptide hormone of the renin-angiotensin system with cardioprotective properties. Studies by us and others showed that Ang-(1-7) improved cardiac function as well as reduced cardiac hypertrophy and fibrosis in various animal models. In this study, we assessed whether adjunct Ang-(1-7) (24 μg/kg/hr) attenuates cardiotoxicity that results from acute (6 week) exposure of 5 week-old Sprague-Dawley rats to Dox, administered weekly at a cumulative dose of 15 mg/kg. Body weight was reduced in rats treated with Dox, in the presence or absence of Ang-(1-7); however, the heart weight/body weight ratio was increased in Dox-treated rats while co-administration with Ang-(1-7) prevented the Dox-mediated increase. Myocyte cross-sectional area was not changed by administration of Dox or Ang-(1-7). Dox administration caused significant increases in cardiac fibrosis (an increase in interstitial fibrosis from 0.9±0.1% to 1.5±0.2%, p<0.001 compared to sham, and perivascular fibrosis from 16.0±1.1% to 23.6±3.0%, p<0.05; n = 3-8), which was prevented by co-administration of Ang-(1-7). Interstitial and perivascular fibrosis in rats treated with Ang-(1-7) or with Dox/Ang-(1-7) was no different than in sham animals. The Dox-mediated increase in cardiac fibrosis and the anti-fibrotic effects of Ang-(1-7) co-administration may account for the changes in heart weight/body weight, since doxorubicin did not alter the size of cardiac myocytes. Cardiac function was assessed using a Vevo 2100 small animal ultrasound system, at baseline and following treatment. Doxorubicin reduced ejection fraction, fractional shortening and cardiac output compared to sham or Ang-(1-7) alone; co-administration of Ang-(1-7) with Dox tended to prevent the Dox-mediated reductions in cardiac contractility. The Dox-mediated increase in fibrosis may contribute to the reduced cardiac contractility and the Ang-(1-7)-mediated reduction in Dox-induced fibrosis may account for the improvement in contractility in rats co-administered Dox and Ang-(1-7). These results suggest that Ang-(1-7) may be effective in preventing Dox-induced cardiac fibrosis and may attenuate acute cardiac toxicity induced by Dox administration. Citation Format: Omeed A. Rahimi, Sharon M. Castellino, Cheryl E. Cammock, E Ann Tallant, Patricia E. Gallagher. Angiotensin-(1-7) prevents fibrosis in doxorubicin-treated rats. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4489. doi:10.1158/1538-7445.AM2015-4489