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(-).
Pino
Paco
P
INSERM U511, Immunobiologie Cellulaire et Moléculaire des Infections Parasitaires, CHU Pitié-Salpêtrière Paris VI, 75013 Paris, France.
Vouldoukis
Ioannis
I
Dugas
Nathalie
N
Hassani-Loppion
Geraldine
G
Dugas
Bernard
B
Mazier
Dominique
D
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000469:parasitology* / Q000502:physiology; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000378:metabolism; D010963:Plasmodium falciparum / Q000472:pathogenicity*; D020545:Respiratory Mucosa / Q000166:cytology / Q000469:parasitology / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D014699:Venules / Q000166:cytology / Q000469:parasitology / Q000502:physiology
D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide