title: Resveratrol Reverses Functional Chagas Heart Disease in Mice.
abstract: 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.
authors: Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia das Interações, Rio de Janeiro, RJ, Brazil.
authors: Glaucia
authors: G
authors: Vilar-Pereira
authors: 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.
authors: Vitor C
authors: VC
authors: Carneiro
authors: UFRJ, Instituto de Microbiologia Paulo de Góes, Departamento de Imunologial, Rio de Janeiro, RJ, Brazil.|UFRJ, Faculdade de Farmácia, Departamento de Análises Clínicas e Toxicológicas, Rio de Janeiro, RJ, Brazil.
authors: Hilton
authors: H
authors: Mata-Santos
authors: 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.
authors: Amanda R R
authors: AR
authors: Vicentino
authors: 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, Centro Nacional de Biologia Estrutural e Bioimagem, Rio de Janeiro, RJ, Brazil.
authors: Isalira P
authors: http://orcid.org/0000-0003-3577-0403
authors: IP
authors: Ramos
authors: UFRJ, Instituto de Bioquímica Médica Leopoldo de Meis, Rio de Janeiro, RJ, Brazil.
authors: Naira L L
authors: http://orcid.org/0000-0002-5986-4861
authors: NL
authors: Giarola
authors: UFRJ, Instituto de Microbiologia Paulo de Góes, Departamento de Imunologial, Rio de Janeiro, RJ, Brazil.
authors: Daniel F
authors: DF
authors: Feijó
authors: UFRJ, Instituto de Bioquímica Médica Leopoldo de Meis, Rio de Janeiro, RJ, Brazil.|Instituto Nacional de Ciência e Tecnologia da Biologia Estrutural e Bioimagem, Rio de Janeiro, RJ, Brazil.
authors: José R
authors: JR
authors: Meyer-Fernandes
authors: UFRJ, Faculdade de Farmácia, Departamento de Fármacos, Rio de Janeiro, RJ, Brazil.
authors: Heitor A
authors: HA
authors: Paula-Neto
authors: UFRJ, Instituto de Biofísica Carlos Chagas Filho, Rio de Janeiro, RJ, Brazil.|UFRJ, Centro Nacional de Biologia Estrutural e Bioimagem, Rio de Janeiro, RJ, Brazil.
authors: Emiliano
authors: E
authors: Medei
authors: UFRJ, Instituto de Microbiologia Paulo de Góes, Departamento de Imunologial, Rio de Janeiro, RJ, Brazil.
authors: Marcelo T
authors: MT
authors: Bozza
authors: Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Biologia das Interações, Rio de Janeiro, RJ, Brazil.
authors: Joseli
authors: J
authors: Lannes-Vieira
authors: UFRJ, Instituto de Microbiologia Paulo de Góes, Departamento de Imunologial, Rio de Janeiro, RJ, Brazil.
authors: Claudia N
authors: CN
authors: Paiva
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002598:Chagas Cardiomyopathy / Q000473:pathology*; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects; D000077185:Resveratrol; D013113:Spin Labels; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D003497:Cyclic N-Oxides; D013113:Spin Labels; D013267:Stilbenes; D008687:Metformin; D000077185:Resveratrol; C001803:tempol