Influência da metformina no metabolismo energético cardíaco de ratos expostos à fumaça de cigarros.
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Data
2018-02-28
Autores
Pires, Vanessa de Cássia Martins [UNESP]
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Universidade Estadual Paulista (Unesp)
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Introdução: A exposição à fumaça de cigarros (EFC) não só aumenta o risco para doenças cardiovasculares como, também, lesa diretamente o miocárdio. Estudos experimentais e clínicos mostram que EFC está associada com hipertrofia e disfunção miocárdica, independentemente de fatores vasculares. Pouco se sabe sobre os mecanismos envolvidos com a lesão miocárdica induzida pela EFC. Dentre estes mecanismos estão as alterações no metabolismo energético. Em um coração normal, 60 a 90% do adenosina trifosfato (ATP) são provenientes da oxidação de ácidos graxos (AG). Em condições patológicas, existem alterações na utilização dos substratos, na biogênese mitocondrial e por fim na produção de ATP, que podem comprometer a morfologia e função cardíaca. Estudos mostram que o tabagismo pode levar a resistência insulínica, que por sua vez pode comprometer a bioenergética cardíaca. Entretanto, não é sabido se há comprometimento do metabolismo energético cardíaco associado à resistência insulínica induzida pela EFC. Adicionalmente, em estudos experimentais, a metformina tem se mostrado eficiente em atenuar a remodelação cardíaca, principalmente atuando sobre o metabolismo energético. Objetivos: Os objetivos do trabalho foi avaliar o papel da metformina na remodelação cardíaca induzida pela fumaça de cigarro, por meio da avaliação morfofuncional cardíaca, do estresse oxidativo, do metabolismo energético, e expressão de proteínas que participam do metabolismo da glicose. Material e Métodos: Foram utilizados 60 animais alocados em 4 grupos de 15 animais cada: grupo EFC (n=15), formado por animais expostos à fumaça do cigarro; EFC-MET (n=15) formado por animais expostos à fumaça do cigarro e com ingestão de metformina diluida na água; grupo controle C (n=15) e grupo MET (n=15) que recebeu metformina diluida em água. Após 2 meses os animais foram submetidos a: a) estudo bioquímico para avaliação da exposição ao cigarro, b) estudo ecocardiográfico para avaliação morfofuncional; c) aferição da pressão arterial caudal; d) estudo histológico utilizando imunofluorescência para avaliação de hipertrofia, angiogenese e translocação de GLUt-4; e) Western Blot para avaliação da expressão de proteínas envolvidas com resistência insulínica e metabolismo da glicose; f) avaliação espectrofotométrica para avaliação da atividade de enzimas do metabolismo energético e da quantidade de glicogênio cardíaco. Resultados: Os animais EFC tiveram aumento do átrio esquerdo (AE), do diâmetro do ventrículo esquerdo (DDVE), da massa do ventrículo esquerdo (IMVE), da espessura relativa da parede posterior (ERP) seguido de disfunção diastólica. A metformina atenuou o tamanho do AE, a ERP, a disfunção diastólica em animais EFC. Em relação aos mecanismos potencialmente envolvidos, observou-se que a EFC aumentou a formação de hidroperóxido de lipídeos, mas a associação com metformina e fumo aumentou ainda mais. Porém a metformina, independentemente da EFC aumentou a atividade das enzimas antioxidantes catalase e superóxido dismutase. Em relação ao metabolismo energético, observou-se que o fumo independentemente da metformina reduziu a atividade do complexo I e ATP sintase. Já a metformina aumentou a atividade do complexo I, II e ATP sintase, independentemente da EFC. Não houve interação entre fumo e metformina para o metabolismo energético. Em relação a expressão de proteínas do metabolismo da glicose observou-se que AKT fosforilado/AKT total e GLUT-4 da membrana diminuíram com o fumo e foram atenuados pela metformina. Conclusão: A metformina atenua os danos gerados pela EFC, provavelmente este fato não ocorre por redução do estresse oxidativo. Existe a possibilidade da EFC induzir alteração do metabolismo da glicose, que no tecido cardíaco fora atenuada pela metformina, talvez por aumentar a fosforilação da AKT e aumento do GLUT-4 na membrana.
Introduction: Exposure to cigarette smoke (ECS) not only increases the risk for cardiovascular disease but also directly damages the myocardium. Experimental and clinical studies show that ECS is associated with hypertrophy and myocardial dysfunction, regardless of vascular factors. Little is known about the mechanisms involved with myocardial injury induced by ECS. Among these mechanisms are the changes in energy metabolism. In a normal heart, 60 to 90% of the adenosine triphosphate (ATP) comes from the fatty acid oxidation (FA). In pathological conditions, there are alterations in the use of substrates, in mitochondrial biogenesis and finally in the production of ATP, which may compromise morphology and cardiac function. Studies show that smoking can lead to insulin resistance, which in turn can compromise cardiac bioenergetics. However, it is not known whether there is impairment of the cardiac energy metabolism associated with the insulin resistance induced by the ECS. Additionally, in experimental studies, metformin has been shown to be effective in attenuating cardiac remodeling, mainly by acting on energy metabolism. Objectives: The objective of this study was to evaluate the role of metformin in cardiac remodeling induced by cigarette smoke through cardiac morphofunctional evaluation, oxidative stress, energy metabolism, and expression of proteins that participate in glucose metabolism. Material and Methods: Sixty animals were allocated to four groups of 15 animals each: ECS group (n = 15), composed of animals exposed to cigarette smoke; ECS-MET (n = 15) consisting of animals exposed to cigarette smoke and with ingestion of metformin diluted in water; group C (n = 15) and MET group (n = 15) who received metformin diluted in water. After 2 months the animals were submitted to: a) biochemical study to evaluate the exposure to cigarette; b) echocardiographic study for morphofunctional evaluation; c) measurement of caudal blood pressure; d) histological study using immunofluorescence to evaluate hypertrophy, angiogenesis and GLUt-4 translocation; e) Western Blot for evaluation of the expression of proteins involved with insulin resistance and glucose metabolism; f) spectrophotometric evaluation to evaluate the activity of energy metabolism enzymes and the amount of cardiac glycogen. RESULTS: ECS animals had left atrial enlargement (AE), left ventricular diameter (LVDD), left ventricular mass (LVMI), relative posterior wall thickness (ERP) followed by diastolic dysfunction. Metformin attenuated the size of AE, ERP, diastolic dysfunction in ECS animals. Regarding the potentially involved mechanisms, it was observed that the ECS increased the formation of lipid hydroperoxide, but the association with metformin and smoke increased even more. However, metformin, independently of the ECS increased the activity of the antioxidant enzymes catalase and superoxide dismutase. Regarding energetic metabolism, it was observed that smoking independently of metformin reduced the activity of complex I and ATP synthase. On the other hand, metformin increased the activity of complex I, II and ATP synthase, independently of the ECS. There was no interaction between smoking and metformin for energy metabolism. Regarding the expression of glucose metabolism proteins, it was observed that phosphorylated AKT / total AKT and membrane GLUT-4 decreased with smoke and were attenuated by metformin. Conclusion: Metformin attenuates the damage generated by the ECS, probably not by reducing oxidative stress. There is a possibility that ECS may induce altered glucose metabolism, which in cardiac tissue has been attenuated by metformin, perhaps by increasing the phosphorylation of AKT and increasing GLUT-4 in the membrane.
Introduction: Exposure to cigarette smoke (ECS) not only increases the risk for cardiovascular disease but also directly damages the myocardium. Experimental and clinical studies show that ECS is associated with hypertrophy and myocardial dysfunction, regardless of vascular factors. Little is known about the mechanisms involved with myocardial injury induced by ECS. Among these mechanisms are the changes in energy metabolism. In a normal heart, 60 to 90% of the adenosine triphosphate (ATP) comes from the fatty acid oxidation (FA). In pathological conditions, there are alterations in the use of substrates, in mitochondrial biogenesis and finally in the production of ATP, which may compromise morphology and cardiac function. Studies show that smoking can lead to insulin resistance, which in turn can compromise cardiac bioenergetics. However, it is not known whether there is impairment of the cardiac energy metabolism associated with the insulin resistance induced by the ECS. Additionally, in experimental studies, metformin has been shown to be effective in attenuating cardiac remodeling, mainly by acting on energy metabolism. Objectives: The objective of this study was to evaluate the role of metformin in cardiac remodeling induced by cigarette smoke through cardiac morphofunctional evaluation, oxidative stress, energy metabolism, and expression of proteins that participate in glucose metabolism. Material and Methods: Sixty animals were allocated to four groups of 15 animals each: ECS group (n = 15), composed of animals exposed to cigarette smoke; ECS-MET (n = 15) consisting of animals exposed to cigarette smoke and with ingestion of metformin diluted in water; group C (n = 15) and MET group (n = 15) who received metformin diluted in water. After 2 months the animals were submitted to: a) biochemical study to evaluate the exposure to cigarette; b) echocardiographic study for morphofunctional evaluation; c) measurement of caudal blood pressure; d) histological study using immunofluorescence to evaluate hypertrophy, angiogenesis and GLUt-4 translocation; e) Western Blot for evaluation of the expression of proteins involved with insulin resistance and glucose metabolism; f) spectrophotometric evaluation to evaluate the activity of energy metabolism enzymes and the amount of cardiac glycogen. RESULTS: ECS animals had left atrial enlargement (AE), left ventricular diameter (LVDD), left ventricular mass (LVMI), relative posterior wall thickness (ERP) followed by diastolic dysfunction. Metformin attenuated the size of AE, ERP, diastolic dysfunction in ECS animals. Regarding the potentially involved mechanisms, it was observed that the ECS increased the formation of lipid hydroperoxide, but the association with metformin and smoke increased even more. However, metformin, independently of the ECS increased the activity of the antioxidant enzymes catalase and superoxide dismutase. Regarding energetic metabolism, it was observed that smoking independently of metformin reduced the activity of complex I and ATP synthase. On the other hand, metformin increased the activity of complex I, II and ATP synthase, independently of the ECS. There was no interaction between smoking and metformin for energy metabolism. Regarding the expression of glucose metabolism proteins, it was observed that phosphorylated AKT / total AKT and membrane GLUT-4 decreased with smoke and were attenuated by metformin. Conclusion: Metformin attenuates the damage generated by the ECS, probably not by reducing oxidative stress. There is a possibility that ECS may induce altered glucose metabolism, which in cardiac tissue has been attenuated by metformin, perhaps by increasing the phosphorylation of AKT and increasing GLUT-4 in the membrane.
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Palavras-chave
metabolismo energético, remodelação cardíaca, fumaça de cigarros, metformina