title: Impairment of the Plasmodium falciparum erythrocytic cycle induced by angiotensin peptides.
abstract: Plasmodium falciparum causes the most serious complications of malaria and is a public health problem worldwide with over 2 million deaths each year. The erythrocyte invasion mechanisms by Plasmodium sp. have been well described, however the physiological aspects involving host components in this process are still poorly understood. Here, we provide evidence for the role of renin-angiotensin system (RAS) components in reducing erythrocyte invasion by P. falciparum. Angiotensin II (Ang II) reduced erythrocyte invasion in an enriched schizont culture of P. falciparum in a dose-dependent manner. Using mass spectroscopy, we showed that Ang II was metabolized by erythrocytes to Ang IV and Ang-(1-7). Parasite infection decreased Ang-(1-7) and completely abolished Ang IV formation. Similar to Ang II, Ang-(1-7) decreased the level of infection in an A779 (specific antagonist of Ang-(1-7) receptor, MAS)-sensitive manner. 10(-7) M PD123319, an AT(2) receptor antagonist, partially reversed the effects of Ang-(1-7) and Ang II. However, 10(-6) M losartan, an antagonist of the AT(1) receptor, had no effect. Gs protein is a crucial player in the Plasmodium falciparum blood cycle and angiotensin peptides can modulate protein kinase A (PKA) activity; 10(-8) M Ang II or 10(-8) M Ang-(1-7) inhibited this activity in erythrocytes by 60% and this effect was reversed by 10(-7) M A779. 10(-6) M dibutyryl-cAMP increased the level of infection and 10(-7) M PKA inhibitor decreased the level of infection by 30%. These results indicate that the effect of Ang-(1-7) on P. falciparum blood stage involves a MAS-mediated PKA inhibition. Our results indicate a crucial role for Ang II conversion into Ang-(1-7) in controlling the erythrocytic cycle of the malaria parasite, adding new functions to peptides initially described to be involved in the regulation of vascular tonus.
authors.affiliation: Instituto Federal de Educação, Ciência e Tecnologia Fluminense, Cabo Frio, Brazil.
authors.forename: Victor Barbosa
authors.initials: VB
authors.lastname: Saraiva
authors.forename: Leandro
authors.initials: L
authors.lastname: de Souza Silva
authors.forename: Claudio Teixeira
authors.initials: CT
authors.lastname: Ferreira-DaSilva
authors.forename: João Luiz
authors.initials: JL
authors.lastname: da Silva-Filho
authors.forename: André
authors.initials: A
authors.lastname: Teixeira-Ferreira
authors.forename: Jonas
authors.initials: J
authors.lastname: Perales
authors.forename: Mariana Conceição
authors.initials: MC
authors.lastname: Souza
authors.forename: Maria das Graças
authors.initials: Md
authors.lastname: Henriques
authors.forename: Celso
authors.initials: C
authors.lastname: Caruso-Neves
authors.forename: Ana Acacia
authors.initials: AA
authors.lastname: de Sá Pinheiro
mesh_terms: D000803:Angiotensin I; D000804:Angiotensin II / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004912:Erythrocytes / Q000187:drug effects* / Q000469:parasitology*; D006801:Humans; D008018:Life Cycle Stages / Q000187:drug effects*; D016778:Malaria, Falciparum / Q000469:parasitology / Q000517:prevention & control; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D052939:Schizonts / Q000187:drug effects / Q000254:growth & development
chemical_list: D010446:Peptide Fragments; D010455:Peptides; D000804:Angiotensin II; D000803:Angiotensin I; C118790:angiotensin I (1-7)