Trypanosoma cruzi induces edematogenic responses in mice and invades cardiomyocytes and endothelial cells in vitro by activating distinct kinin receptor subtypes (B-1/B-2)

Trypanosoma cruzi, the protozoan that causes Chagas' heart disease, invades endothelial cells in vitro by activating the B-2 kinin receptor (B2R). Here, we demonstrate that mice infected with trypomastigotes develop potent edema after treatment with the angiotensin-converting enzyme (ACE) (or kininase II) inhibitor captopril. Experiments performed with specific kinin receptor (B2R/B1R) antagonists and knockout mice revealed that the early-phase (3-h) edema is mediated by the constitutive B2R, whereas the late-phase (24-h) response depends on stimulation of the up-regulated B1R. Given previous evidence that parasite invasion of cells expressing B2R is potentiated by captopril, we investigated the prerequisites for in vitro infection of Chinese hamster ovary cells overexpressing either B1R or B2R, human umbilical vein endothelial cells activated by lipopolysaccharide, and neonatal rat cardiomyocytes. Our results indicate that captopril potentiates parasite invasion regardless of the kinin (B-2/B-1) activation pathways, whereas DL-2-mercaptomethyl-3-guanidino-ethylthiopropanoic acid (MGTA), an inhibitor of kininase I (carboxypeptidase M/N), selectively decreases parasite infectivity for B1R-expressing cells. These data suggest that formation of the B1R agonist, i.e., [des-Arg] kinins, critically depends on the processing action of kininase I, here proposed as a potential pathogenesis cofactor. Collectively, our data suggest that fluctuations in the levels of kininases may modulate parasite infectivity and pathological outcome in Chagas' disease.Univ Brasil, CCS, Inst Biofis Carlos Chagas Filho, BR-21944900 Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Dept Biofis, Escola Paulista Med, São Paulo, BrazilMax Delbruck Ctr Mol Med, Berlin, GermanyUniv Colorado, Sch Med, Dept Biochem & Mol Genet, Denver, CO 80262 USAUniv Frankfurt, Sch Med, Inst Biochem 2, D-6000 Frankfurt, GermanyUniv Rio de Janeiro, Dept Biol Celular & Genet, Rio de Janeiro, BrazilFundacao Oswaldo Cruz, Inst Oswaldo Cruz, Rio de Janeiro, BrazilUniversidade Federal de São Paulo, Dept Biofis, Escola Paulista Med, São Paulo, BrazilWeb of Scienc