Department of Physiology, University of Alberta, Edmonton, Canada.
Cardiovasc Res. 2010 Jan 1;85(1):194-203. doi: 10.1093/cvr/cvp277.
Preeclampsia is a hypertensive disorder characterized by vascular oxidative stress. Decreased availability of the vasodilator nitric oxide (NO) has been postulated to be involved in the pathophysiology of this disorder. Arginase, an enzyme that competes with nitric oxide synthase (NOS) for l-arginine, not only reduces NO formation but also increases superoxide production by NOS. In placenta of preeclamptic women, arginase upregulation has been shown to be increased and contributes to superoxide formation via uncoupling of NOS. However, the role of arginase in the maternal vasculature is not clear. We hypothesized that arginase would be upregulated in the maternal vasculature of women with preeclampsia and contribute to oxidative stress within the endothelium.
We observed increased arginase expression in the maternal vasculature of women with preeclampsia compared with normotensive pregnant women. Furthermore, human umbilical vein endothelial cells treated with 2% plasma from preeclamptic women show increased arginase II expression and activity that was reduced by a peroxynitrite scavenger. Also, both 3-morpholino sydnonimine and exogenous peroxynitrite increased arginase expression and activity. Preeclamptic plasma treatment increased superoxide and peroxynitrite levels. Superoxide levels were significantly reduced after arginase and NOS inhibition with [(S)-(2-boronoethyl)-l-cysteine] and N(omega)-nitro-l-arginine methyl ester, respectively, but peroxynitrite levels were in fact increased after arginase inhibition. Moreover, in the presence of preeclamptic plasma, l-arginine supplementation increased peroxynitrite formation during arginase inhibition.
Increased arginase expression in preeclampsia can induce uncoupling of NOS as a source of superoxide in the maternal vasculature in preeclampsia. However, l-arginine supplementation in the face of oxidative stress could lead to a further increase in peroxynitrite.
子痫前期是一种以血管氧化应激为特征的高血压疾病。据推测，血管舒张因子一氧化氮（NO）的供应减少与该疾病的病理生理学有关。精氨酸酶是一种与一氧化氮合酶（NOS）竞争 l-精氨酸的酶，不仅会减少 NO 的形成，还会增加 NOS 的超氧化物产生。在子痫前期妇女的胎盘组织中，已显示出精氨酸酶的上调增加，并通过 NOS 的解偶联促进超氧化物的形成。然而，精氨酸酶在母体血管中的作用尚不清楚。我们假设，子痫前期妇女的母体血管中的精氨酸酶会上调，并导致内皮细胞内的氧化应激。
我们观察到，与正常妊娠妇女相比，子痫前期妇女的母体血管中精氨酸酶的表达增加。此外，用来自子痫前期妇女的 2%血浆处理人脐静脉内皮细胞，显示出精氨酸酶 II 的表达和活性增加，而过氧化物硝化物清除剂可降低其表达和活性。此外，3-吗啉代-sydnonimine 和外源性过氧亚硝酸盐均可增加精氨酸酶的表达和活性。子痫前期血浆处理增加了超氧化物和过氧亚硝酸盐的水平。在用[(S)-(2-硼代乙基)-l-半胱氨酸]和 N(ω)-硝基-l-精氨酸甲酯分别抑制精氨酸酶和 NOS 后，超氧化物水平显著降低，但在用精氨酸酶抑制剂后，过氧亚硝酸盐水平实际上增加。此外，在子痫前期血浆存在的情况下，补充 l-精氨酸会增加精氨酸酶抑制时的过氧亚硝酸盐形成。
子痫前期中精氨酸酶表达的增加会导致母体血管中 NOS 的解偶联，从而产生超氧化物。然而，在面对氧化应激时，l-精氨酸的补充可能会导致过氧亚硝酸盐进一步增加。
