Resveratrol Reverses Functional Chagas Heart Disease in Mice

PLoS Pathogens

Glaucia Vilar-Pereira¹  Joseli Lannes-Vieira²  José R. Meyer-Fernandes³  Amanda R. R. Vicentino⁴  Claudia N. Paiva⁵  Naira L. L. Giarola⁶  Daniel F. Feijó⁷  Heitor A. Paula-Neto⁸  Marcelo T. Bozza⁸  Hilton Mata-Santos⁹  Emiliano Medei⁹  Vitor C. Carneiro^1,10  Isalira P. Ramos^1,10 

[1] Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia das Interações, Rio de Janeiro, RJ, Brazil;Instituto Nacional de Ciência e Tecnologia da Biologia Estrutural e Bioimagem, Rio de Janeiro, RJ, Brazil;UFRJ, Centro Nacional de Biologia Estrutural e Bioimagem, Rio de Janeiro, RJ, Brazil;UFRJ, Faculdade de Farmácia, Departamento de Análises Clínicas e Toxicológicas, Rio de Janeiro, RJ, Brazil;UFRJ, Faculdade de Farmácia, Departamento de Fármacos, Rio de Janeiro, RJ, Brazil;UFRJ, Hospital Universitário Clementino Fraga Filho, Departamento de Radiologia, Rio de Janeiro, RJ, Brazil;UFRJ, Instituto de Biofísica Carlos Chagas Filho, Rio de Janeiro, RJ, Brazil;UFRJ, Instituto de Bioquímica Médica Leopoldo de Meis, Rio de Janeiro, RJ, Brazil;UFRJ, Instituto de Microbiologia Paulo de Góes, Departamento de Imunologial, Rio de Janeiro, RJ, Brazil;Universidade Federal do Rio de Janeiro (UFRJ), Instituto de Bioquímica Médica Leopoldo de Meis, Programa de Biologia Molecular e Tecnologia, Rio de Janeiro, RJ, Brazil

关键词: Heart;    Parasitic diseases;    Cardiac ventricles;    Chagas disease;    Cardiovascular diseases;    Electrocardiography;    Oxidative stress;    Trypanosoma cruzi;   

DOI  :  10.1371/journal.ppat.1005947

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Chronic chagasic cardiomyopathy (CCC) develops years after acute infection by Trypanosoma cruzi and does not improve after trypanocidal therapy, despite reduction of parasite burden. During disease, the heart undergoes oxidative stress, a potential causative factor for arrhythmias and contractile dysfunction. Here we tested whether antioxidants/ cardioprotective drugs could improve cardiac function in established Chagas heart disease. We chose a model that resembles B1-B2 stage of human CCC, treated mice with resveratrol and performed electrocardiography and echocardiography studies. Resveratrol reduced the prolonged PR and QTc intervals, increased heart rates and reversed sinus arrhythmia, atrial and atrioventricular conduction disorders; restored a normal left ventricular ejection fraction, improved stroke volume and cardiac output. Resveratrol activated the AMPK-pathway and reduced both ROS production and heart parasite burden, without interfering with vascularization or myocarditis intensity. Resveratrol was even capable of improving heart function of infected mice when treatment was started late after infection, while trypanocidal drug benznidazole failed. We attempted to mimic resveratrol’s actions using metformin (AMPK-activator) or tempol (SOD-mimetic). Metformin and tempol mimicked the beneficial effects of resveratrol on heart function and decreased lipid peroxidation, but did not alter parasite burden. These results indicate that AMPK activation and ROS neutralization are key strategies to induce tolerance to Chagas heart disease. Despite all tissue damage observed in established Chagas heart disease, we found that a physiological dysfunction can still be reversed by treatment with resveratrol, metformin and tempol, resulting in improved heart function and representing a starting point to develop innovative therapies in CCC.

【 授权许可】

CC BY