Influence of omega 3 fatty acid supplementation on attenuation of doxorubicin-induced cardiotoxicity in rats: role of the ceramide pathway

Author(s)

Marina Gaiato Monte

• Document type: Master's Dissertation
• Press: Botucatu. 2021-07-16.
• Institution: Universidade Estadual Paulista (Unesp). Faculdade de Medicina. Botucatu
• Defense date: 2021-06-11
• Advisor: Bertha Furlan Polegato

Abstract

Cardiotoxicity is the most serious side effect of treatment with the chemotherapy drug doxorubicin. The identification of mechanisms involved in the pathophysiology of cardiotoxicity allows the discovery of mitigation strategies for this complication. Ceramides are formed from the degradation of sphingolipids in cell membranes and play an important role in signaling and modulating biological processes, including oxidative stress. There is evidence that the administration of omega 3 fatty acids can act with the membranes and interfere with this cellular damage pathway. Objective: To evaluate the influence of omega 3 fatty acid supplementation in the attenuation of chronic cardiotoxicity induced by doxorubicin in rats. Additionally, we evaluated the involvement of the ceramide pathway in the pathophysiology of cardiac injury and the possible protective effect of omega 3 fatty acids. Material and Methods: 60 male Wistar rats were divided into 4 groups: Control (C), Doxorubicin (D), Omega 3 (W), Doxorubicin + Omega 3 (DW). The groups received omega 3 fatty acids (400 mg/kg/day, via gavage) or water for 6 weeks and doxorubicin (3.5 mg/kg, intraperitoneally, 1x/week) or saline for 4 weeks. At the end of 6 weeks, an echocardiogram and euthanasia were performed to collect the biological material. The activity of the sphingomyelinase enzyme (SMase), serum concentrations of lipids and creatinine, Comet assay, oxidative stress, nSMase1 were evaluated by immunohistochemistry and determination of the expression of nSMase1 (neutral sphingomyelinase 1) and IkB (inhibitor of kappa factor B) by Western Blot. Statistical analysis: 2- way ANOVA. Results: there was less feed intake and weight loss in animals that received doxorubicin. In animals treated with chemotherapy, we observed an increase in the left atrium and left ventricle (LV), serum triglycerides and cholesterol, malonaldehyde (a marker of oxidative damage to lipids), protein carbonylation (a marker of oxidative damage to proteins), a decrease of the LV shortening fraction and lower expression of the nSMase1 enzyme in the heart. Omega 3 supplementation attenuated the structural and functional changes caused by doxorubicin and decreased protein carbonylation. Omega 3 also decreased the intensity and moment of the tail in the comet assay and increased the neutral nSMase activity in both animals that received and those that did not receive doxorubicin. Conclusion: Omega 3 fatty acid supplementation attenuated chronic cardiotoxicity caused by doxorubicin in rats. Possibly, the ceramide pathway is involved in the pathophysiology of cardiotoxicity, but it is not the mechanism by which omega 3 fatty acid attenuated cardiac dysfunction. (AU)

• FAPESP's process: 18/25677-7 - Influence of omega 3 in doxorubicin-induced cardiotoxicity in rats: role of ceramide pathway
• Grantee: Marina Gaiato Monte
• Support Opportunities: Scholarships in Brazil - Master