@MASTERSTHESIS{ 2020:681362910,
 	title = {Impact of renin-angiotensin system modulators on Trypanosoma cruzi infection in vitro and in vivo},
 	year = {2020},
 	url = "https://bdtd.unifal-mg.edu.br:8443/handle/tede/1807",
 	abstract = "American trypanosomiasis or Chagas disease is caused by the protozoan Trypanosoma cruzi. 
 This disease is endemic in Latin America and about 8 million people are infected worldwide. 
 Acute infections are often asymptomatic and deaths are uncommon. Conversely, chronic 
 cardiomyopathy is the most severe clinical manifestation of Chagas disease, which if related to 
 heart failure and death. Currently, the etiological treatment is limited to benznidazole and 
 nifurtmox, which present high toxicity and low cure rates in chronic infections (10-20%). In 
 patients with chronic cardiomyopathy, renin-angiotensin system (RAS) modulating drugs, such 
 as angiotensin-converting enzyme (ACE) inhibitors, are used to improve cardiovascular 
 function. Interestingly, these drugs have also been associated with better parasitological control 
 and attenuation of myocarditis in T. cruzi-infected hosts. Although these drugs are 
 immunomodulatory, it is still poorly understood whether antitrypanosomal effects are due to an 
 enhanced immune response or direct antiparasitic effects. Thus, we used a systematic review 
 framework and an in vitro and in vivo experimental approach to evaluate the impact of RAS 
 modulating drugs on T. cruzi infection. According to our systematic review, captopril, losartan 
 and enalapril increase parasite uptake by host cells, upregulate IL-12 and IFN-γ expression and 
 downregulate IL-10 and IL-17 production by leukocytes in vitro. In infected animals, the 
 studies reviewed indicated a marked reduction of parasitemia, tissue parasitism, inflammation 
 and mortality. In our experimental models, our in vitro findings indicated that ramipril and 
 losartan increased cardiomyocytes infection rate. Surprisingly, the angiotensin-(1-7) antagonist 
 A-779 was able to reduce trypomastigotes viability, cardiomyocytes infection and the endocytic 
 index. The angiotensin’s II and 1-7 had no effect on T. cruzi infection, while the ECA activator 
 diminazene aceturate (DMZ) had a toxic dose-dependent effect on trypomastigotes. Our in vivo
 findings indicated that ramipril and DMZ did not prevented myocarditis or interfere with 
 parasitemia peak, IgG plasma levels, and animal weight loss. However, both drugs reduced 
 hepatomegaly, cardiomegaly and mortality in infected mice; while ramipril also attenuated 
 skeletal myositis compared to infected untreated animals. Taken together, our findings supports 
 the evidence that RAS modulating drugs, but not angiotensin’s II and 1-7, exerts antiparasitic
 effects in vitro potentially mediated by indirect immunomediated processes, as well as by direct 
 toxic effects on infective forms of T. cruzi. However, the antiparasitic effect of ramipril and 
 DMZ observed in vitro did not manifest in our murine model of T. cruzi infection, indicating 
 limited relevance of these drugs to the treatment of experimental Chagas disease.",
 	publisher = {Universidade Federal de Alfenas},
 	scholl = {Programa de Pós-graduação em Ciências Biológicas},
 	note = {Instituto de Ciências da Natureza}
}