Redox-dependent apoptosis in human endothelial cells after adhesion of Plasmodium falciparum-infected erythrocytes.

During Plasmodium falciparum infection leading to cerebral malaria, mechanisms such as cytokine generation and cytoadherence of parasitized red blood cells (PRBC) to post-capillary venules are clearly involved. We demonstrated that PRBC adhesion to human lung endothelial cells (HLEC) upregulated TNF-alpha superfamily genes and genes related to apoptosis and inflammation. Apoptosis was confirmed by standard techniques (annexin-V binding, genomic DNA fragmentation, and caspases activation). This apoptotic process involved the cytoplasmic pathway from a death receptor (DR-6, Fas, TNF-R1) through caspase 8, and the mitochondrial pathway though Bad and caspase 9 activation. Oxidative stress has been implicated in apoptosis induction in various pathological models. Superoxide anion (O(2)*(-)) is a key molecule in the oxidative stress pathway which can form peroxynitrites (ONOO(-)) in association with nitric oxide (NO*). Even though the role of NO* in malaria physiopathology is still a matter of controversy, we demonstrated that PRBC-induced apoptosis in endothelial cells is mediated through an oxidative stress pathway. The inhibition of NO* synthesis protected the endothelial cells suggesting a deleterious role for NO*. In addition, the superoxide dismutase mimetic, MnTBAP, also protected the HLEC against PRBC-induced apoptosis, revealing the role of O(2)*(-) and ONOO(-).