Angiotensin-(1–7) reduces doxorubicin-induced cardiac dysfunction in male and female Sprague-Dawley rats through antioxidant mechanisms

Abstract

Doxorubicin (Dox) is an effective chemotherapeutic for a variety of pediatric malignancies. Unfortunately, Dox administration often results in a cumulative dose-dependent cardiotoxicity that manifests with marked oxidative stress, leading to heart failure. Adjunct therapies are needed to mitigate Dox cardiotoxicity and enhance quality of life in pediatric patients with cancer. Angiotensin-(1–7) [Ang-(1–7)] is an endogenous hormone with cardioprotective properties. This study investigated whether adjunct Ang-(1–7) attenuates cardiotoxicity resulting from exposure to Dox in male and female juvenile rats. Dox significantly reduced body mass, and the addition of Ang-(1–7) had no effect. However, adjunct Ang-(1–7) prevented Dox-mediated diastolic dysfunction, including markers of decreased passive filling as measured by reduced early diastole mitral valve flow velocity peak ( E) ( P < 0.05) and early diastole mitral valve annulus peak velocity ( e′; P < 0.001) and increased E/e′ ( P < 0.001), an echocardiographic measure of diastolic dysfunction. Since Dox treatment increases reactive oxygen species (ROS), the effect of Ang-(1–7) on oxidative by-products and enzymes that generate or reduce ROS was investigated. In hearts of male and female juvenile rats, Dox increased NADPH oxidase 4 ( P < 0.05), a major cardiovascular NADPH oxidase isozyme that generates ROS, as well as 4-hydroxynonenal ( P < 0.001) and malondialdehyde ( P < 0.001), markers of lipid peroxidation; Ang-(1–7) prevented these effects of Dox. Cotreatment with Dox and Ang-(1–7) increased the antioxidant enzymes SOD1 (male: P < 0.05; female: P < 0.01) and catalase ( P < 0.05), which likely contributed to reduced ROS. These results demonstrate that Ang-(1–7) prevents diastolic dysfunction in association with a reduction in ROS, suggesting that the heptapeptide hormone may serve as an effective adjuvant to improve Dox-induced cardiotoxicity. NEW & NOTEWORTHY Ang-(1–7) is a clinically safe peptide hormone with cardioprotective and antineoplastic properties that could be used as an adjuvant therapy to improve cancer treatment and mitigate the long-term cardiotoxicity associated with doxorubicin in pediatric patients with cancer.