title: Simvastatin Attenuates Endothelial Activation through 15-Epi-Lipoxin A4 Production in Murine Chronic Chagas Cardiomyopathy.
abstract: Current treatments for chronic Chagas cardiomyopathy, a disease with high mortality rates and caused by the protozoanTrypanosoma cruzi, are unsatisfactory. Myocardial inflammation, including endothelial activation, is responsible for the structural and functional damage seen in the chronic phase. The clinical efficacy of benznidazole could be improved by decreasing chronic inflammation. Statins, which have anti-inflammatory properties, may improve the action of benznidazole. Here, the action of simvastatin in a murine model of chronic Chagas cardiomyopathy and the link with the production of the proresolving eicosanoid 15-epi-lipoxin A4, produced by 5-lipoxygenase, are evaluated. Simvastatin decreased the expression of the adhesion molecules E-selectin, intracellular adhesion molecule type 1 (ICAM-1), and vascular cell adhesion molecule type 1 (VCAM-1) inT. cruzi-infected mice. However, when this drug was administered to 5-lipoxygenase-deficient mice, the anti-inflammatory effect was not observed unless exogenous 15-epi-lipoxin A4 was administered. Thus, in chronic Chagas disease, 5-epi-lipoxin A4 induced by simvastatin treatment could improve the pathophysiological condition of patients by increasing the trypanocidal action of benznidazole.
authors.affiliation: Programa de Farmacología Molecular y Clínica-ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Fabiola
authors.initials: F
authors.lastname: González-Herrera
authors.affiliation: Program in Health Sciences: Infectious Diseases and Tropical Medicine, Medical School, and Departments of Biochemistry and Immunology, Microbiology, and Pathology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Allysson
authors.initials: A
authors.lastname: Cramer
authors.affiliation: Program in Health Sciences: Infectious Diseases and Tropical Medicine, Medical School, and Departments of Biochemistry and Immunology, Microbiology, and Pathology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Pollyana
authors.initials: P
authors.lastname: Pimentel
authors.affiliation: Programa de Anatomía y Biología del Desarrollo-ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Christian
authors.initials: C
authors.lastname: Castillo
authors.affiliation: Programa de Anatomía y Biología del Desarrollo-ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Ana
authors.initials: A
authors.lastname: Liempi
authors.affiliation: Programa de Anatomía y Biología del Desarrollo-ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kemmerling
authors.affiliation: Program in Health Sciences: Infectious Diseases and Tropical Medicine, Medical School, and Departments of Biochemistry and Immunology, Microbiology, and Pathology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
authors.forename: Fabiana S
authors.initials: FS
authors.lastname: Machado
authors.affiliation: Programa de Farmacología Molecular y Clínica-ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile jmaya@med.uchile.cl.
authors.forename: Juan D
authors.identifier: 0000-0003-3934-6319
authors.initials: JD
authors.lastname: Maya
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency / Q000235:genetics; D002598:Chagas Cardiomyopathy / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000469:parasitology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D005786:Gene Expression Regulation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D044045:Lipoxins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009593:Nitroimidazoles / Q000494:pharmacology*; D018512:Parasitemia / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000469:parasitology; D019821:Simvastatin / Q000494:pharmacology*; D016019:Survival Analysis; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D019040:E-Selectin; C090509:Icam1 protein, mouse; D044045:Lipoxins; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; D019010:Vascular Cell Adhesion Molecule-1; C040527:lipoxin A4; D018799:Intercellular Adhesion Molecule-1; D019821:Simvastatin; D001094:Arachidonate 5-Lipoxygenase; C009999:benzonidazole
keywords: 15-epi-lipoxin A4; 5-lipoxygenase; CAM; Chagas disease; chronic cardiomyopathy; simvastatin