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 AT2 receptor antagonist, partially reversed the effects of Ang-(1–7) and Ang II. However, 10−6 M losartan, an antagonist of the AT1 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.

Quantitative Variation in Plasma Angiotensin‐I Converting Enzyme Activity Shows Allelic Heterogeneity in the ABO Blood Group Locus

“…In this regard it is of interest that angiotensin-II has recently been shown to reduce erythrocyte invasion in vitro by P. falciparum in a dosedependent manner, and that the deletion allele of the ACE insertion/deletion polymorphism, which is associated with higher plasma ACE activity, has been reported to be protective against cerebral malaria (Dhangadamajhi et al, 2010;Saraiva et al, 2011). Further research into the question of whether the major genetic effects on plasma ACE activity at the ACE and ABO loci contribute significantly to differential susceptibility to severe malaria would be of interest.…”

Effects of the angiotensin II Ala-scan analogs in erythrocytic cycle of Plasmodium falciparum (in vitro) and Plasmodium gallinaceum (ex vivo)

“…Twenty-four hours after treatment all peptides were able to reduce new ring formation at 10 −8 M concentration, which was studied by Saraiva et al as the ideal concentration for these inhibition assays (Saraiva et al, 2011). The tests were carried out in duplicate and a total of ten experiments were performed (n = 10).…”

“…Saraiva et al have described studies that aimed at identifying the molecular mechanisms induced by Ang II, which are involved in the modulation of P. falciparum erythrocytic cycle. The results showed that Ang II have had some influence in the parasite ring forms reduction (47%) (Saraiva et al, 2011). Silva et al tested Alascan Ang II analogs to verify the importance of each residue of the Ang II native molecule and the intra and intermolecular peptide interactions with P. gallinaceum sporozoites.…”

Linear Peptides Related to Angiotensin II with Antiplasmodial Activity

“…Angiotensin II cannot be used as an antimalarial drug due to its vasoconstrictor effect [1,2]. Ten peptides related to it were synthesized by Fmoc solid phase strategy, purified by RP-HPLC, characterized by LC/ESI-MS and tested against mature Plasmodium gallinaceum sporozoites and Plasmodium falciparum early throphozoites.…”