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Sustainable Development Goals
03 Saúde e Bem-EstarCollections
- IOC - Artigos de Periódicos [12725]
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GENETIC ABLATION AND PHARMACOLOGICAL BLOCKADE OF BRADYKININ B1 RECEPTOR UNVEILED A DETRIMENTAL ROLE FOR THE KININ SYSTEM IN CHAGAS DISEASE CARDIOMYOPATHY
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Abstract
Chagas disease, the parasitic infection caused by Trypanosoma cruzi, afflicts about 6 million
people in Latin America. Here, we investigated the hypothesis that T. cruzi may fuel heart parasitism
by activating B1R, a G protein-coupled (brady) kinin receptor whose expression is upregulated in
inflamed tissues. Studies in WT and B1R/ mice showed that T. cruzi DNA levels (15 days post
infection—dpi) were sharply reduced in the transgenic heart. FACS analysis revealed that frequencies
of proinflammatory neutrophils and monocytes were diminished in B1R/ hearts whereas
CK-MB activity (60 dpi) was exclusively detected in B1R+/+ sera. Since chronic myocarditis and
heart fibrosis (90 dpi) were markedly attenuated in the transgenic mice, we sought to determine
whether a pharmacological blockade of the des-Arg9-bradykinin (DABK)/B1R pathway might alleviate
chagasic cardiomyopathy. Using C57BL/6 mice acutely infected by a myotropic T. cruzi strain
(Colombian), we found that daily treatment (15–60 dpi) with R-954 (B1R antagonist) reduced heart
parasitism and blunted cardiac injury. Extending R-954 treatment to the chronic phase (120–160 dpi),
we verified that B1R targeting (i) decreased mortality indexes, (ii) mitigated chronic myocarditis, and
(iii) ameliorated heart conduction disturbances. Collectively, our study suggests that a pharmacological
blockade of the proinflammatory KKS/DABK/B1R pathway is cardioprotective in acute and
chronic Chagas disease.
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