Dysregulation of L-arginine metabolism and bioavailability associated to free plasma heme.
Severe Plasmodium falciparum malaria is associated with hypoargininemia, which contributes to impaired systemic and pulmonary nitric oxide (NO) production and endothelial dysfunction. Since intravascular hemolysis is an intrinsic feature of severe malaria, we investigated whether and by which mechanisms free heme [Fe(III)-protoporphyrin IX (FP)] might contribute to the dysregulation of L-arginine (L-Arg) metabolism and bioavailability. Carrier systems "y+" [or cationic amino acid transporter (CAT)] and "y+L" transport L-Arg into red blood cells (RBC), where it is hydrolyzed to ornithine and urea by arginase (isoform I) or converted to NO* and citrulline by endothelial nitric oxide synthase (eNOS). Our results show a significant and dose-dependent impairment of L-Arg transport into RBC pretreated with FP, with a strong inhibition of the system carrier y+L. Despite the impaired L-Arg influx, higher amounts of L-Arg-derived urea are produced by RBC preexposed to FP caused by activation of RBC arginase I. This activation appeared not to be mediated by oxidative modifications of the enzyme. We conclude that L-Arg transport across RBC membrane is impaired and arginase-mediated L-Arg consumption enhanced by free heme. This could contribute to reduced NO production in severe malaria.
Omodeo-Salè
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F
Dipartimento di Scienze Molecolari Applicate ai Biosistemi (DISMAB), Facoltà di Farmacia, Università di Milano, Milan, Italy. fausta.omodeosale@unimi.it
Cortelezzi
L
L
Vommaro
Z
Z
Scaccabarozzi
D
D
Dondorp
A M
AM
D027182:Amino Acid Transport System y+ / Q000097:blood; D027241:Amino Acid Transport System y+L / Q000097:blood; D001119:Arginase / Q000097:blood; D001120:Arginine / Q000097:blood*; D001682:Biological Availability; D001692:Biological Transport; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D004789:Enzyme Activation; D004912:Erythrocytes / Q000378:metabolism*; D006427:Hemin / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D016778:Malaria, Falciparum / Q000097:blood*; D055806:Microvessels / Q000166:cytology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009952:Ornithine / Q000097:blood; D014508:Urea / Q000097:blood
D027182:Amino Acid Transport System y+; D027241:Amino Acid Transport System y+L; D002956:Citrulline; D009569:Nitric Oxide; D006427:Hemin; D014508:Urea; D001120:Arginine; D009952:Ornithine; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D001119:Arginase