Impairment of the Plasmodium falciparum erythrocytic cycle induced by angiotensin peptides

• Published in: PloS one Vol. 6; no. 2; p. e17174
• Main Authors: Saraiva, Victor Barbosa, de Souza Silva, Leandro, Ferreira-DaSilva, Claudio Teixeira, da Silva-Filho, João Luiz, Teixeira-Ferreira, André, Perales, Jonas, Souza, Mariana Conceição, Henriques, Maria das Graças, Caruso-Neves, Celso, de Sá Pinheiro, Ana Acacia
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.02.2011; Public Library of Science (PLoS)
• Subjects: Angiotensin; Angiotensin I; Angiotensin II; Angiotensin II - chemistry; Angiotensin II - pharmacology; Angiotensin II - therapeutic use; Angiotensins; Animals; Antigens; Biology; Blood; Cells, Cultured; Complications; Cyclic adenosine monophosphate; Cyclic AMP; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzymes; Erythrocytes; Erythrocytes - drug effects; Erythrocytes - parasitology; Guanine nucleotide-binding protein; Health aspects; Humans; Infections; Kinases; Laboratories; Life Cycle Stages - drug effects; Malaria; Malaria, Falciparum - parasitology; Malaria, Falciparum - prevention & control; Mass spectrometry; Mass spectroscopy; Parasites; Parasitic diseases; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; Peptides; Peptides - pharmacology; Peptides - therapeutic use; Phenols; Physiological aspects; Plasmodium; Plasmodium falciparum; Plasmodium falciparum - drug effects; Plasmodium falciparum - growth & development; Plasmodium falciparum - physiology; Protein kinase A; Protein kinases; Proteins; Public health; Radioisotopes; Rats; Renin; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - physiology; Schizonts - drug effects; Schizonts - growth & development; Spectroscopy; Vector-borne diseases; Brazil; Rio de Janeiro Brazil
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0017174

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.