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

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 Do...

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Bibliographic Details
Published in:American journal of physiology. Heart and circulatory physiology 2020-04, Vol.318 (4), p.H883-H894
Main Authors: Rahimi, Omeed, Kirby, Jay, Varagic, Jasmina, Westwood, Brian, Tallant, E Ann, Gallagher, Patricia E
Format: Article
Language:English
Subjects:
4-Hydroxynonenal
Angiotensin
Angiotensin I - therapeutic use
Animals
Antineoplastic Agents - toxicity
Antioxidants
Antioxidants - therapeutic use
Body mass
Cancer
Cardiotoxicity
Catalase
Catalase - metabolism
Diastole
Doxorubicin
Doxorubicin - toxicity
Enzymes
Female
Flow velocity
Heart diseases
Heart Diseases - drug therapy
Heart Diseases - etiology
Heart Rate
Heart valves
Indicator species
Lipid peroxidation
Lipids
Male
Malondialdehyde
Malondialdehyde - metabolism
Markers
Mitral valve
Mitral Valve - physiopathology
Myocardium - metabolism
NAD(P)H oxidase
NADPH Oxidases - genetics
NADPH Oxidases - metabolism
Oxidase
Oxidative stress
Patients
Pediatrics
Peptide Fragments - therapeutic use
Peroxidation
Quality of life
Rats
Rats, Sprague-Dawley
Reactive oxygen species
Reactive Oxygen Species - metabolism
Rodents
Superoxide dismutase
Superoxide Dismutase - metabolism
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Summary: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 ( ) ( < 0.05) and early diastole mitral valve annulus peak velocity ( ; < 0.001) and increased ( < 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 ( < 0.05), a major cardiovascular NADPH oxidase isozyme that generates ROS, as well as 4-hydroxynonenal ( < 0.001) and malondialdehyde ( < 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: < 0.05; female: < 0.01) and catalase ( < 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. 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.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00224.2019