Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.
Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.
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DOI：
10.1371/journal.ppat.1005119
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发表时间：
2015-09
期刊：
影响因子：
6.7
通讯作者：
Ackerman H
中科院分区：
文献类型：
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作者：
Chertow JH;Alkaitis MS;Nardone G;Ikeda AK;Cunnington AJ;Okebe J;Ebonyi AO;Njie M;Correa S;Jayasooriya S;Casals-Pascual C;Billker O;Conway DJ;Walther M;Ackerman H
一氧化氮（NO）信号的抑制可能有助于在严重疟疾感染的血管内皮细胞的病理激活。二甲基精氨酸二甲氨基水解酶（DDAH）通过维持内源性NO合酶（NOS）抑制剂不对称二甲基精氨酸（ADMA）和NOS底物精氨酸之间的稳态来调节内皮细胞NO的合成。我们对冈比亚儿童进行了一项以社区为基础的病例对照研究，以确定在严重或无并发症的疟疾感染期间ADMA和精氨酸稳态是否被破坏。ADMA和精氨酸的循环血浆水平测定在最初的介绍和28天后。与28天随访值相比，急性重症疟疾儿童的血浆ADMA/精氨酸比值升高，与无并发症疟疾儿童或健康儿童相比（每次比较p<0.0001）。为了检验DDAH 1在疟原虫感染过程中失活的假设，我们在严重疟疾的小鼠模型中检测了DDAH 1。伯氏疟原虫ANKA感染通过转录后机制灭活肝脏DDAH 1，表现为稳定的mRNA转录本数量、DDAH 1蛋白浓度降低、酶活性降低、组织ADMA升高、血浆中ADMA/精氨酸比值升高和全血亚硝酸盐浓度降低。肝脏DDAH 1活性的丧失和ADMA/精氨酸稳态的破坏可能通过抑制NO合成而导致严重疟疾发病。在疟疾感染期间，血管内皮变得更具粘附性、渗透性，并且易于触发血液凝固。这些变化有助于寄生虫粘附在血管上，但通过阻碍小血管的血液流动而危及宿主。内皮一氧化氮（NO）通常会抵消这些病理变化，但NO信号减弱疟疾。NO的合成受到不对称二甲基精氨酸（ADMA）的抑制，ADMA是一种精氨酸的甲基化衍生物，在正常蛋白质周转期间释放。我们发现，冈比亚儿童严重疟疾，代谢紊乱，抑制NO合成的ADMA精氨酸的比例升高。ADMA与内皮激活和受损组织灌注的标志物相关。在使用小鼠的平行实验中，负责代谢ADMA的酶，二甲基精氨酸二甲基氨基水解酶（DDAH）在感染啮齿动物疟疾后被灭活。基于这些研究，我们提出，DDAH的ADMA代谢降低可能有助于在疟疾急性发作期间观察到的ADMA/精氨酸比值升高。保持或增加DDAH活性的策略可能会改善NO的合成，并有助于预防严重疟疾的血管表现。
Inhibition of nitric oxide (NO) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor, and arginine, the NOS substrate. We carried out a community-based case-control study of Gambian children to determine whether ADMA and arginine homeostasis is disrupted during severe or uncomplicated malaria infections. Circulating plasma levels of ADMA and arginine were determined at initial presentation and 28 days later. Plasma ADMA/arginine ratios were elevated in children with acute severe malaria compared to 28-day follow-up values and compared to children with uncomplicated malaria or healthy children (p<0.0001 for each comparison). To test the hypothesis that DDAH1 is inactivated during Plasmodium infection, we examined DDAH1 in a mouse model of severe malaria. Plasmodium berghei ANKA infection inactivated hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue ADMA, elevated ADMA/arginine ratio in plasma, and decreased whole blood nitrite concentration. Loss of hepatic DDAH1 activity and disruption of ADMA/arginine homeostasis may contribute to severe malaria pathogenesis by inhibiting NO synthesis. During a malaria infection, the vascular endothelium becomes more adhesive, permeable, and prone to trigger blood clotting. These changes help the parasite adhere to blood vessels, but endanger the host by obstructing blood flow through small vessels. Endothelial nitric oxide (NO) would normally counteract these pathological changes, but NO signalling is diminished malaria. NO synthesis is inhibited by asymmetric dimethylarginine (ADMA), a methylated derivative of arginine that is released during normal protein turnover. We found the ratio of ADMA to arginine to be elevated in Gambian children with severe malaria, a metabolic disturbance known to inhibit NO synthesis. ADMA was associated with markers of endothelial activation and impaired tissue perfusion. In parallel experiments using mice, the enzyme responsible for metabolizing ADMA, dimethylarginine dimethylaminohydrolase (DDAH), was inactivated after infection with a rodent malaria. Based on these studies, we propose that decreased metabolism of ADMA by DDAH might contribute to the elevated ADMA/arginine ratio observed during an acute episode of malaria. Strategies to preserve or increase DDAH activity might improve NO synthesis and help to prevent the vascular manifestations of severe malaria.