Influência da suplementação do ácido graxo ômega 3 na atenuação da cardiotoxicidade induzida pela doxorrubicina em ratos: papel da via da ceramida
Carregando...
Arquivos
Data
2021-06-11
Autores
Monte, Marina Gaiato
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
A cardiotoxicidade é o efeito colateral mais grave do tratamento com o quimioterápico doxorrubicina. A identificação dos mecanismos envolvidos na fisiopatologia da cardiotoxicidade permite a descoberta de estratégias de atenuação dessa complicação. As ceramidas são formadas a partir da degradação dos esfingolipídeos das membranas celulares e tem importante papel na sinalização e modulação de processos biológicos, incluindo estresse oxidativo. Há evidências que a administração de ácidos graxos ômega 3 possa atuar junto às membranas e interferir com essa via de dano celular. Objetivo: avaliar a influência da suplementação de ácidos graxos ômega 3 na atenuação da cardiotoxicidade crônica induzida pela doxorrubicina em ratos. Adicionalmente, avaliamos o envolvimento da via da ceramida na patofisiologia da lesão cardíaca e no possível efeito protetor dos ácidos graxos ômega 3. Material e Métodos: 60 ratos Wistar machos foram alocados em 4 grupos: Controle (C), Doxorrubicina (D), Ômega 3 (W), Doxorrubicina + Ômega 3 (DW). Os grupos receberam ácidos graxos ômega 3 (400 mg/kg/dia, via gavagem) ou água por 6 semanas e doxorrubicina (3,5 mg/kg, intraperitoneal, 1x/semana) ou salina por 4 semanas. Ao final de 6 semanas, foi realizado ecocardiograma e eutanásia para coleta do material biológico. Foram avaliadas a atividade da enzima esfingomielinase (SMase), as concentrações séricas de lipídeos e creatinina, ensaio Cometa, estresse oxidativo, nSMase1 por imuno-histoquímica e determinação da expressão de nSMase1 (esfingomielinase neutra 1) e IkB (inibidor do fator kappa B) por Western Blot. Análise estatística: ANOVA de 2 vias. Resultados: houve menor ingestão de ração e perda de peso nos animais que receberam doxorrubicina. Nos animais tratados com o quimioterápico observamos aumento do átrio esquerdo e o ventrículo esquerdo (VE), dos triglicerídeos e colesterol séricos, do malonaldeído (marcador do dano oxidativo aos lipídeos), da carbonilação de proteínas (marcador do dano oxidativo às proteínas), diminuição da fração de encurtamento do VE e menor expressão da enzima nSMase1 no coração. A suplementação de ômega 3 atenuou as alterações estruturais e funcionais provocadas pela doxorrubicina e diminuiu a carbonilação de proteínas. O ômega 3 também diminuiu a intensidade e o momento da cauda no ensaio cometa e aumentou a atividade da nSMase neutra tanto nos animais que receberam quanto nos que não receberam a doxorrubicina. Conclusão: a suplementação de ácido graxo ômega 3 atenuou a cardiotoxicidade crônica provocada pela doxorrubicina em ratos. Possivelmente, a via da ceramida está envolvida na fisiopatologia da cardiotoxicidade, mas não é o mecanismo pelo qual o ácido graxo ômega 3 atenuou a disfunção cardíaca.
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.
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.
Descrição
Palavras-chave
Estresse oxidativo, Esfingomielinas, Dislipidemia, Doxorrubicina, Cardiotoxicidade crônica, Ácidos graxos ômega 3, Oxidative stress, Sphingomyelin, Dyslipidemia, Doxorubicin, Chronic cardiotoxicity, Omega 3 fatty acids