Vascular nitric oxide (NO) bioavailability is decreased in severe falciparum malaria and associated with microvascular dysfunction, increased activation of the cells lining blood vessels (endothelial cells) and increased parasite biomass. Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthase (NOS) enzymatic conversion of L-arginine to NO and L-citrulline. But when BH4 is low, NOS is “uncoupled” and produces superoxide instead of NO. In oxidative conditions, BH4 is oxidized to dihydrobiopterin (BH2) and biopterin (B0). BH2 competes with remaining BH4 at its NOS binding site, further decreasing NOS-catalyzed NO production. We measured BH4, BH2 and B0 in the urine of children with coma due to falciparum malaria (cerebral malaria), uncomplicated falciparum malaria, children with non-malaria central nervous system conditions and healthy controls. Urine BH4 was significantly decreased and BH2 significantly increased in cerebral malaria compared to uncomplicated malaria, non-malaria central nervous conditions and healthy controls, suggesting increased oxidative stress and insufficient recycling of BH2 back to BH4. Urine BH4 concentration was independently associated with increased risk of cerebral malaria. Given that safe therapies for regenerating BH4 have been studied in chronic vascular disease, this finding of low BH4 in pediatric cerebral malaria offers a new area of investigation for adjunctive therapies aimed at improving NO bioavailability and, consequently, clinical outcomes in severe falciparum malaria.
Vyšlo v časopise: Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Oxidized Biopterins in Pediatric Falciparum Malaria: Association with Disease Severity. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004655 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004655
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