Doxorubicin (Dox) is an effective chemotherapeutic agent for various malignancies including childhood leukemias and lymphomas. Unfortunately, Dox administration often results in a cumulative dose-dependent cardiotoxicity that manifests as cardiomyopathy with marked oxidative stress and fibrosis leading to a long-term reduction in cardiovascular function and heart failure. Adjunct therapies to mitigate Dox-induced cardiotoxicity and enhance long-term quality-of-life in cancer patients are needed, particularly for pediatric patients. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous heptapeptide hormone of the renin-angiotensin system with cardioprotective properties. We investigated whether adjunct Ang-(1-7) attenuates cardiotoxicity resulting from acute (6 week) exposure to Dox (21-24 mg/kg) in male and female juvenile rats (n = 7-10). Dox treatment reduced body/heart mass in male and female rats and co-administration of Ang-(1-7) had no effect on these morphological changes. However, co-administration of the heptapeptide hormone prevented Dox-mediated diastolic dysfunction, including decreased passive filling (E; 16%, p<0.05) and mitral annulus tissue movement (e'; 45% in males and 31% in females, p<0.001) and the subsequent increased filling pressure (E/e'; 47% in males and 43% in females, p<0.001). In both male and female rat hearts, Dox administration increased NADPH oxidase 4 (Nox4; 2-fold in males and females, p<0.05), the major Nox isozyme that generates ROS in the heart, as well as 4-hydroxynonenal (4-HNE; 7.5-fold in males and 3.5-fold in females, p<0.001) and malondialdehyde (MDA; 20-fold in males and 15-fold in females, p<0.001), markers of lipid peroxidation. Co-administration of Ang-(1-7) prevented these effects of Dox while Ang-(1-7) alone had no effect. Treatment of rats with Dox and Ang-(1-7) also increased cardiac superoxide dismutase 1 (SOD1; 4-fold in males and 5-fold in females, p<0.05 and p<0.01 respectively) and catalase (10-fold in males and 4-fold in females, p<0.05), further contributing to reduced oxidative stress. Oxidative stress is associated with an increase in cardiac fibrosis, a maladaptive change that exacerbates cardiac dysfunction. Treatment of male and female rats with Dox increased collagen deposition in the heart which was associated with an increase in the fibrogenic cytokine TGF-β1 and TGF-β1-activated phospho-SMAD2; co-administration of Ang-(1-7) mitigated the Dox-induced increase in fibrosis while the heptapeptide hormone alone had no effect. The anti-oxidant and anti-fibrotic effects of Ang-(1-7) may account for the improvement in diastolic function by the heptapeptide hormone, suggesting that treatment with Ang-(1-7) may serve as an effective adjuvant to improve Dox-induced cardiac dysfunction.
Citation Format: Patricia E. Gallagher, Omeed Rahimi, Brian Westwood, Jay Kirby, Jasmina Varagic, Elisabeth Ann Tallant. Angiotensin-(1-7) prevents doxorubicin-induced cardiotoxicity by reducing oxidative stress and fibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2885.