| Summary: | <p>Abstract</p> <p>Background</p> <p>The malaria burden remains a major public health concern, especially in sub-Saharan Africa. The complex biology of <it>Plasmodium</it>, the apicomplexan parasite responsible for this disease, challenges efforts to develop new strategies to control the disease. Proteolysis is a fundamental process in the metabolism of malaria parasites, but roles for proteases in generating vasoactive peptides have not previously been explored.</p> <p>Results</p> <p>In the present work, it was demonstrated by mass spectrometry analysis that <it>Plasmodium</it> parasites (<it>Plasmodium chabaudi</it> and <it>Plasmodium falciparum</it>) internalize and process plasma kininogen, thereby releasing vasoactive kinins (Lys-BK, BK and des-Arg<sup>9</sup>-BK) that may mediate haemodynamic alterations during acute malaria. In addition, it was demonstrated that the <it>P. falciparum</it> cysteine proteases falcipain-2 and falcipain-3 generated kinins after incubation with human kininogen, suggesting that these enzymes have an important role in this process. The biologic activity of peptides released by <it>Plasmodium</it> parasites was observed by measuring ileum contraction and activation of kinin receptors (B1 and B2) in HUVEC cells; the peptides elicited an increase in intracellular calcium, measured by Fluo-3 AM fluorescence. This effect was suppressed by the specific receptor antagonists Des-Arg<sup>9</sup>[Leu<sup>8</sup>]-BK and HOE-140.</p> <p>Conclusions</p> <p>In previously undescribed means of modulating host physiology, it was demonstrated that malaria parasites can generate active kinins by proteolysis of plasma kininogen.</p>
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