Binding of endothelin-1 to the lipid moiety of haemozoin and P. falciparum parasitised red blood cells

Plasmodium falciparum infection may evolve into severe disease if untreated or inadequately treated, causing an estimated one million deaths annually. The severe forms of malaria are characterized by the release of inflammatory cytokines and the cytoadherence of parasitized red blood cells (pRBC) to the vascular endothelium. This results in the sequestration of pRBCs in various organs causing micro-circulatory obstruction and subsequent tissue hypoxia. Endothelin1 (ET-1) is a 21 amino acid peptide produced by the vascular endothelium under hypoxia, that acts locally as regulator of vascular tone and inflammation. The role of ET-1 in falciparum malaria is still controversial and largely unknown, although tissue hypoxia is frequent as a result of the sequestration of pRBC to the microvasculature. In the present work, we show that both synthetic and endothelial-derived ET-1 are removed by pRBC and native haemozoin (malaria pigment), but not by normal RBC, delipidized haemozoin or synthetic beta-haematin. The effect is selective for ET-1, but not for its precursor, bigET-1, and not due to a direct binding to ET-A or ET-B receptors. These findings may help understand the consequences of parasite sequestration in severe malaria. The financial support of AntiMal EU 188134 is acknowledged