Potential cardioprotective effects and lipid mediator differences in long-chain omega-3 polyunsaturated fatty acid supplemented mice given chemotherapy

Authors: ANGELOTTI, AUSTIN - The Ohio State University; SNOKE, DEENA - The Ohio State University; ORMISTON, KATE - The Ohio State University; COLE, RACHEL - The Ohio State University; BORKOWSKI, KAMIL - University Of California, Davis; Newman, John; ORCHARD, TONYA - The Ohio State University; BELURY, MARTHA - The Ohio State University

Submitted to: Metabolites
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/22/2022
Publication Date: 8/24/2022
Citation: Angelotti, A., Snoke, D., Ormiston, K., Cole, R., Borkowski, K., Newman, J.W., Orchard, T., Belury, M.A. 2022. Potential cardioprotective effects and lipid mediator differences in long-chain omega-3 polyunsaturated fatty acid supplemented mice given chemotherapy. Metabolites. 12(9). Article 782. https://doi.org/10.3390/metabo12090782.
DOI: https://doi.org/10.3390/metabo12090782

Interpretive Summary: Many commonly used chemotheraputic drugs cause the heart muscle mitochondria to function poorly, leading to heart failure later in life. Dietary long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) have demonstrated cardioprotective function in non-chemotherapy models of heart failure. Metabolites of the LC n-3 PUFAs may be responsible for these protective effects. However, it is unknown whether dietary supplementation with LC n-3 PUFA can protect the heart from chemotherapy-induced toxicity. To test this, 36 female ovariectomized C57BL/6J mice were fed diets containing either 0 or a 12.2 g/kg LC n-3 PUFA, and received either vehicle or two chemotherapy treatments. Body weight, food intake, heart gene expression, and fatty acid composition were measured. Lipid mediator of cell growth and inflammation were measured in isolated heart mitochondria. LC n-3 PUFA supplementation attenuated some chemotherapy-induced heart gene expression, and significantly altered various lipid species in cardiac mitochondrial preparations, including several epoxy fatty acids and N-acylethanolamines, suggesting a possible functional link between heart lipids and cardiotoxicity.

Technical Abstract: Many commonly used chemotherapies induce mitochondrial dysfunction in cardiac muscle which leads to cardiotoxicity and heart failure later in life. Dietary long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) have demonstrated cardioprotective function in non-chemotherapy models of heart failure, potentially through formation of LC n-3 PUFA-derived bioactive lipid me-tabolites. However, it is unknown whether dietary supplementation with LC n-3 PUFA can pro-tect against chemotherapy-induced cardiotoxicity. To test this, 36 female ovariectomized C57BL/6J mice were randomized in a two-by-two factorial design to either a low (0 g/kg EPA+DHA) or high (12.2 g/kg EPA+DHA) LC n-3 PUFA diets, and received either two vehicle or two chemotherapy (9 mg/kg anthracycline + 90 mg/kg cyclophosphamide) intraperitoneal injec-tions separated by two weeks. Body weight and food intake were measured, as well as heart gene expression, and fatty acid composition. Heart mitochondria were extracted using differential cen-trifugation and targeted lipidomic analysis was performed on mitochondrial isolates. LC n-3 PUFA supplementation attenuated some chemotherapy-induced differences (Myh7, Col3a1) in heart gene expression, and significantly altered various lipid species in cardiac mitochondrial preparations, including several epoxy fatty acids and N-acylethanolamines, suggesting a possible functional link between heart lipids and cardiotoxicity.