Genetic Ablation and Pharmacological Blockade of Bradykinin B1 Receptor Unveiled a Detrimental Role for the Kinin System in Chagas Disease Cardiomyopathy

• Published in: Journal of clinical medicine Vol. 12; no. 8; p. 2888
• Main Authors: Oliveira, Ana Carolina, Vicentino, Amanda Roberta Revoredo, Andrade, Daniele, Pereira, Isabela Resende, Saboia-Vahia, Leonardo, Moreira, Otacílio da Cruz, Carvalho-Pinto, Carla Eponina, Mota, Julia Barbalho da, Maciel, Leonardo, Vilar-Pereira, Glaucia, Pesquero, João B, Lannes-Vieira, Joseli, Sirois, Pierre, Campos de Carvalho, Antônio Carlos, Scharfstein, Julio
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 15.04.2023; MDPI
• Subjects: Blood vessels; Bradykinin; Cardiomyocytes; Cardiomyopathy; Cardiovascular agents; Cell receptors; Chagas disease; Clinical medicine; Dendritic cells; Diabetes; Drug therapy; Enzymes; Genetic aspects; Health aspects; Heart; Heart diseases; Heparan sulfate; Infections; Lymphocytes; Parasites; Parasitic diseases; Pathogens; Protozoa; Smooth muscle; Testing; Brazil; Chagas disease; bradykinin; GPCRs; kallikrein; Trypanosoma cruzi
• ISSN: 2077-0383; 2077-0383
• DOI: 10.3390/jcm12082888

Chagas disease, the parasitic infection caused by , afflicts about 6 million people in Latin America. Here, we investigated the hypothesis that 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 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-Arg -bradykinin (DABK)/B1R pathway might alleviate chagasic cardiomyopathy. Using C57BL/6 mice acutely infected by a myotropic 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.