Influência da empagliflozina sobre à remodelação cardíaca induzida por infarto do miocárdio em ratos
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2021-08-26
Autores
Damatto, Felipe César
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Universidade Estadual Paulista (Unesp)
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Introdução: O infarto do miocárdio (IM) está entre as principais causas de mortalidade no mundo e, quando não evolui a óbito, pode resultar em remodelação cardíaca e insuficiência cardíaca. Estudos recentes com inibidores seletivos da proteína co-transportadora de sódio-glicose tipo 2 (SGLT2), usados no tratamento de diabetes, sugerem possível melhora de agravo cardiovascular devido à atenuação da remodelação cardíaca. Os efeitos benéficos podem ser devido às alterações no metabolismo energético, glicemia, adiposidade visceral, concentração sérica de insulina, pressão sanguínea, estresse oxidativo, função endotelial, progressão de doença renal, e a possibilidade de modular beneficamente proteínas co-transportadoras de cálcio no coração. O presente estudo teve o objetivo de avaliar os efeitos do inibidor da SGLT2 empagliflozina (EMP) sobre o coração de ratos submetido à remodelação cardíaca induzida por IM. Métodos: Foram constituídos quatro grupos de ratos Wistar machos: sem infarto (SHAM; n=22); sem infarto e com EMP (SHAM+EMP; n=22); com infarto (IM; n=22); com infarto e com EMP (IM+EMP; n=22). EMP foi adicionada à ração na dose de 5 mg/kg/dia, durante 12 semanas. Dez dias após o infarto e ao final do período experimental foram realizados ecocardiogramas transtorácicos. Foi realizada análise histológica para determinar o tamanho do infarto, fração colágena intersticial e tamanho dos cardiomiócitos. As análises do estresse oxidativo, do metabolismo energético e a atividade do complexo respiratório foram realizadas em miocárdio do ventrículo esquerdo por espectrofotometria. As comparações entre os grupos foram realizadas por ANOVA de duas vias. A comparação entre o tamanho dos infartos foi realizada pelo teste t de Student. Para análise de frequência de sinais clínicos foi usado o teste de Goodman. Resultados: Os animais infartados tratados apresentaram maior consumo de ração e água e maior taxa glicêmica que os ratos infartados não tratados. No entanto, o peso corporal não foi diferente entre os grupos ao final do estudo. A efusão pleural foi observada em 50% dos ratos do grupo IM e nenhum caso no grupo IM+EMP (p<0,01). A EMP não causou diferença no tamanho dos infartos, na fração colágena intersticial e no diâmetro dos cardiomiócitos. Em relação as variáveis ecocardiográficas, o tratamento com EMP reduziu o diâmetro do átrio esquerdo em animais infartados. As demais variáveis não mostraram diferença estatística com o tratamento. O estresse oxidativo, avaliado pela concentração miocárdica de hidroperóxido de lipídeo foi menor no grupo IM+EMP em relação ao grupo IM. No entanto, as enzimas antioxidantes catalase, superóxido dismutase e glutationa peroxidase não se alteraram com a EMP. Nos grupos infartados, as enzimas do metabolismo energético lactato desidrogenase e citrato sintase mostraram-se elevados, e a enzima beta hidroxiacil-CoA desidrogenase se mostrou reduzida. Não houve diferença significante entre os grupos infartados. O complexo respiratório I, II e ATP sintase não foi diferente entre os grupos infartados. Conclusão: No modelo de infarto do miocárdio em ratos não diabéticos, a empagliflozina diminui o diâmetro do átrio esquerdo, melhora o estresse oxidativo e evita a ocorrência de derrame pleural que é um dos sinais de insuficiência cardíaca congestiva.
Introduction: Myocardial infarction (MI) is one of the main causes of mortality worldwide and, when it does not progress to death, it may result in cardiac remodeling and heart failure. Recent studies with selective inhibitors of sodium-glucose cotransporter type 2 (SGLT2), a drug indicated for diabetic patients, suggest a possible beneficial effects in cardiovascular injury due to attenuation of cardiac remodeling. Among these effects include improvement of energy metabolism, blood glucose, visceral adiposity, serum insulin concentration, blood pressure, oxidative stress, endothelial function, renal disease progression, and calcium co-transporter modulation in the heart. The aim of this study was to evaluate the effects of the SGLT2 inhibitor empagliflozin (EMP) on the heart of rats undergoing cardiac remodeling induced by MI. Methods: Wistar rats were divided into four groups: non-infarcted rats (SHAM; n=22); non-infarcted rats with EMP (SHAM+EMP; n=22); infarcted rats (MI; n=22); infarcted rats with EMP (MI+EMP; n=22). EMP was added to rat chow (5 mg/kg/day) for 12 weeks. Echocardiograms were performed ten days after infarction and at the end of experiment. Histological analysis was performed to measure infarct size, interstitial collagen fraction, and cardiomyocyte diameter. Analyzes of oxidative stress, energy metabolism, and respiratory complex activity were performed in left ventricular myocardium by spectrophotometry. Comparisons between groups were performed by two-way ANOVA. Comparison between infarct sizes was performed using Student's t test. The Goodman test was used for frequency analysis. Results: Treated infarcted animals showed higher chow and water intake, and higher blood glucose than untreated infarcted rats. However, body weight was not different between groups at the end of study. Pleural effusion was observed in 50% of MI group rats and none of MI+EMP group (p<0.01). EMP caused no difference in infarct size, interstitial collagen fraction, and cardiomyocyte diameter. Echocardiogram showed that EMP reduced the left atrial diameter in infarcted animals. Other echocardiographic variables showed no statistical difference between infarcted groups. Myocardial lipid hydroperoxide concentration was lower in MI+EMP group compared to MI group. However, antioxidant enzymes catalase, superoxide dismutase, and glutathione peroxidase did not change with EMP. The energy metabolism enzymes lactate dehydrogenase and citrate synthase were higher and beta hydroxyacyl-CoA dehydrogenase enzyme lower in infarcted groups compared to non-infarcted. However, there was no significant difference between the infarcted groups. Respiratory complex I, II, and ATP synthase were not different between the infarcted groups. Conclusion: In myocardial infarction model in non-diabetic rats, empagliflozin reduces the left atrial diameter, improves oxidative stress, and prevents pleural effusion, which is one of the signs of congestive heart failure.
Introduction: Myocardial infarction (MI) is one of the main causes of mortality worldwide and, when it does not progress to death, it may result in cardiac remodeling and heart failure. Recent studies with selective inhibitors of sodium-glucose cotransporter type 2 (SGLT2), a drug indicated for diabetic patients, suggest a possible beneficial effects in cardiovascular injury due to attenuation of cardiac remodeling. Among these effects include improvement of energy metabolism, blood glucose, visceral adiposity, serum insulin concentration, blood pressure, oxidative stress, endothelial function, renal disease progression, and calcium co-transporter modulation in the heart. The aim of this study was to evaluate the effects of the SGLT2 inhibitor empagliflozin (EMP) on the heart of rats undergoing cardiac remodeling induced by MI. Methods: Wistar rats were divided into four groups: non-infarcted rats (SHAM; n=22); non-infarcted rats with EMP (SHAM+EMP; n=22); infarcted rats (MI; n=22); infarcted rats with EMP (MI+EMP; n=22). EMP was added to rat chow (5 mg/kg/day) for 12 weeks. Echocardiograms were performed ten days after infarction and at the end of experiment. Histological analysis was performed to measure infarct size, interstitial collagen fraction, and cardiomyocyte diameter. Analyzes of oxidative stress, energy metabolism, and respiratory complex activity were performed in left ventricular myocardium by spectrophotometry. Comparisons between groups were performed by two-way ANOVA. Comparison between infarct sizes was performed using Student's t test. The Goodman test was used for frequency analysis. Results: Treated infarcted animals showed higher chow and water intake, and higher blood glucose than untreated infarcted rats. However, body weight was not different between groups at the end of study. Pleural effusion was observed in 50% of MI group rats and none of MI+EMP group (p<0.01). EMP caused no difference in infarct size, interstitial collagen fraction, and cardiomyocyte diameter. Echocardiogram showed that EMP reduced the left atrial diameter in infarcted animals. Other echocardiographic variables showed no statistical difference between infarcted groups. Myocardial lipid hydroperoxide concentration was lower in MI+EMP group compared to MI group. However, antioxidant enzymes catalase, superoxide dismutase, and glutathione peroxidase did not change with EMP. The energy metabolism enzymes lactate dehydrogenase and citrate synthase were higher and beta hydroxyacyl-CoA dehydrogenase enzyme lower in infarcted groups compared to non-infarcted. However, there was no significant difference between the infarcted groups. Respiratory complex I, II, and ATP synthase were not different between the infarcted groups. Conclusion: In myocardial infarction model in non-diabetic rats, empagliflozin reduces the left atrial diameter, improves oxidative stress, and prevents pleural effusion, which is one of the signs of congestive heart failure.
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Palavras-chave
Infarto, Remodelação cardíaca, Estresse oxidativo, Metabolismo energético, SGLT2, Empagliflozina, Infarction, Cardiac remodeling, Oxidative stress, Energy metabolism, Empagliflozin