Impaired systemic tetrahydrobiopterin bioavailability and increased dihydrobiopterin in adult falciparum malaria: association with disease severity, impaired microvascular function and increased endothelial activation.
Impaired systemic tetrahydrobiopterin bioavailability and increased dihydrobiopterin in adult falciparum malaria: association with disease severity, impaired microvascular function and increased endothelial activation.
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DOI：
10.1371/journal.ppat.1004667
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发表时间：
2015-03
期刊：
影响因子：
6.7
通讯作者：
Anstey NM
中科院分区：
文献类型：
--
作者：
Yeo TW;Lampah DA;Kenangalem E;Tjitra E;Price RN;Weinberg JB;Hyland K;Granger DL;Anstey NM
四氢生物蝶呤(BH4)是一氧化氮合酶(NOS)和氨基酸单加氧酶(包括苯丙氨酸羟基酶)催化活性所必需的辅因子。BH4是不稳定的：在氧化应激期间，它被非酶氧化为二氢生物蝶呤(BH2)，后者抑制一氧化氮合酶。根据BH4的可获得性，NOS在NO合成酶和NADPH氧化酶之间振荡：随着BH4/BH2比率的降低，NO产量下降，并被超氧化物取代。在患有严重疟疾的非洲儿童和亚洲成人中，NO的生物利用度降低，血浆苯丙氨酸增加，共同表明可能缺乏BH4。尚未在恶性疟疾中评估主要的三种生物蝶呤代谢物(BH4、BH2和B0[生物蝶呤])及其与疾病严重程度的关系。我们测定了12例成人重度恶性疟疾(SM；n=12)、17例中重度疟疾(MSM，n=17)、5例重度败血症(SS；n=5)和20例健康人(HC；n=20)的尿蝶呤代谢物。与MSM(中位数0.27)、SS(中位数0.54)和HC(中位数0.34)相比，SM患者尿中BH4降低(中位数0.16mol/mmolScinine)；p<；0.001。相反，与MSM(中位数0.67)、SS(中位数0.39)和HC(中位数0.52)相比，SM(中位数0.91moL/mmolcreatinine)的BH2升高；P<；0.001，这表明在严重疟疾中，BH2增加了氧化应激，BH2没有充分地循环回到BH4。总体而言，与MSM(0.45，IQR0.27-61)、SS(1.03；IQR0.54-2.38)和对照组(0.66；IQR0.43-1.07)相比，SM的BH4/BH2中值最低[0.18(IQR0.04-0.32)]；p<；0.001。在疟疾中，较低的BH4/BH2比值与微血管反应性降低(r=0.41p=0.03)和ICAM-1升高(r=-0.52p=0.005)相关。在严重疟疾(但不是严重败血症)中，BH4减少和BH2增加，导致NO的生物利用度受损，并可能增加氧化应激。再生BH4的辅助治疗可能在改善严重恶性疟疾患者的NO生物利用度和微血管灌流方面发挥作用。严重恶性疟疾患者的血管一氧化氮(NO)生物利用度降低，并与微血管功能障碍和血管内皮细胞激活增加有关。一氧化氮合酶(NOS)需要四氢生物蝶呤(BH4)作为辅助因子将L-精氨酸转化为NO，但当BH4较低时，NOS是解偶联的，产生超氧化物而不是NO。在氧化应激增加的情况下，BH4被转化为二氢生物蝶呤(BH2)和生物蝶呤(B0)：生成的BH2与剩余的BH4竞争，作为一氧化氮合酶(NOS)的竞争性抑制物，进一步减少NO的产生。我们检测了患有严重和无并发症恶性疟疾的成人尿液中的BH4和BH2，并将结果与对照组或败血症患者进行了比较。与无并发症的疟疾、败血症和对照组相比，重度疟疾患者尿中BH4显著减少，BH2显著增加，提示氧化应激增加，BH2未充分循环回到BH4。BH4/BH2比值与严重疾病、内皮激活和微血管功能障碍的风险增加相关，可能是通过受损的NOS功能。在重症疟疾中降低NO的这一额外机制表明，评估在重症疟疾中使用辅助剂L精氨酸来增加NO的试验可能需要同时治疗以再生BH4。
Tetrahydrobiopterin (BH4) is a co-factor required for catalytic activity of nitric oxide synthase (NOS) and amino acid-monooxygenases, including phenylalanine hydroxylase. BH4 is unstable: during oxidative stress it is non-enzymatically oxidized to dihydrobiopterin (BH2), which inhibits NOS. Depending on BH4 availability, NOS oscillates between NO synthase and NADPH oxidase: as the BH4/BH2 ratio decreases, NO production falls and is replaced by superoxide. In African children and Asian adults with severe malaria, NO bioavailability decreases and plasma phenylalanine increases, together suggesting possible BH4 deficiency. The primary three biopterin metabolites (BH4, BH2 and B0 [biopterin]) and their association with disease severity have not been assessed in falciparum malaria. We measured pterin metabolites in urine of adults with severe falciparum malaria (SM; n=12), moderately-severe malaria (MSM, n=17), severe sepsis (SS; n=5) and healthy subjects (HC; n=20) as controls. In SM, urinary BH4 was decreased (median 0.16 ¼mol/mmol creatinine) compared to MSM (median 0.27), SS (median 0.54), and HC (median 0.34)]; p<0.001. Conversely, BH2 was increased in SM (median 0.91 ¼mol/mmol creatinine), compared to MSM (median 0.67), SS (median 0.39), and HC (median 0.52); p<0.001, suggesting increased oxidative stress and insufficient recycling of BH2 back to BH4 in severe malaria. Overall, the median BH4/BH2 ratio was lowest in SM [0.18 (IQR: 0.04-0.32)] compared to MSM (0.45, IQR 0.27-61), SS (1.03; IQR 0.54-2.38) and controls (0.66; IQR 0.43-1.07); p<0.001. In malaria, a lower BH4/BH2 ratio correlated with decreased microvascular reactivity (r=0.41; p=0.03) and increased ICAM-1 (r=-0.52; p=0.005). Decreased BH4 and increased BH2 in severe malaria (but not in severe sepsis) uncouples NOS, leading to impaired NO bioavailability and potentially increased oxidative stress. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria. Vascular nitric oxide (NO) bioavailability is decreased in severe falciparum malaria and associated with microvascular dysfunction and increased endothelial activation. Nitric oxide synthase (NOS) requires tetrahydrobiopterin (BH4) as a co-factor to convert L-arginine to NO, but when BH4 is low, NOS is “uncoupled” and produces superoxide instead of NO. In conditions of increased oxidative stress, BH4 is converted to dihydrobiopterin (BH2) and biopterin (B0): the resulting BH2 competes with remaining BH4 as a competitive inhibitor of NOS, further decreasing NO production. We measured BH4 and BH2 in the urine of adults with severe and uncomplicated falciparum malaria and compared results to those of controls or those with sepsis. There was a significant decrease in urinary BH4 and increase in BH2 in severe malaria compared to uncomplicated malaria, sepsis, and controls, suggesting increased oxidative stress and insufficient recycling of BH2 back to BH4. The BH4/BH2 ratio was associated with increased risk of severe disease, endothelial activation and microvascular dysfunction, likely through impaired NOS function. This additional mechanism of decreased NO in severe malaria suggests that trials evaluating use of adjunctive L-arginine to increase NO in severe malaria may require concurrent therapy to regenerate BH4.
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DOI：
10.1016/j.niox.2011.04.004
发表时间：
2011-08-01
期刊：
Nitric oxide : biology and chemistry
影响因子：
--
作者：
Crabtree MJ;Channon KM
通讯作者：
Channon KM
影响因子：
168.9
作者：
Dondorp, Arjen M.;Fanello, Caterina I.;White, Nicholas J.
通讯作者：
White, Nicholas J.
影响因子：
8.8
作者：
Charunwatthana P;Abul Faiz M;Ruangveerayut R;Maude RJ;Rahman MR;Roberts LJ 2nd;Moore K;Bin Yunus E;Hoque MG;Hasan MU;Lee SJ;Pukrittayakamee S;Newton PN;White NJ;Day NP;Dondorp AM
通讯作者：
Dondorp AM
影响因子：
4.2
作者：
Opladen, Thomas;Abu Seda, Bettina;Blau, Nenad
通讯作者：
Blau, Nenad