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Role of oxidative stress in the dysfunction of the placental endothelial Nitric Oxide synthase in preeclampsia
Redox Biology ( IF 11.4 ) Pub Date : 2021-01-19 , DOI: 10.1016/j.redox.2021.101861
Paul Guerby 1 , Oriane Tasta 2 , Audrey Swiader 3 , Frédéric Pont 4 , Emmanuel Bujold 5 , Olivier Parant 6 , Christophe Vayssiere 6 , Robert Salvayre 3 , Anne Negre-Salvayre 3
Affiliation  

Preeclampsia (PE) is a multifactorial pregnancy disease, characterized by new-onset gestational hypertension with (or without) proteinuria or end-organ failure, exclusively observed in humans. It is a leading cause of maternal morbidity affecting 3-7% of pregnant women worldwide. PE pathophysiology could result from abnormal placentation due to a defective trophoblastic invasion and an impaired remodeling of uterine spiral arteries, leading to a poor adaptation of utero-placental circulation. This would be associated with hypoxia/reoxygenation phenomena, oxygen gradient fluctuations, altered antioxidant capacity, oxidative stress, and reduced nitric oxide (NO) bioavailability. This results in part from the reaction of NO with the radical anion superoxide (O2•−), which produces peroxynitrite ONOO-, a powerful pro-oxidant and inflammatory agent. Another mechanism is the progressive inhibition of the placental endothelial nitric oxide synthase (eNOS) by oxidative stress, which results in eNOS uncoupling via several events such as a depletion of the eNOS substrate L-arginin due to increased arginase activity, an oxidation of the eNOS cofactor tetrahydrobiopterin (BH4), or eNOS post-translational modifications (for instance by S-glutathionylation). The uncoupling of eNOS triggers a switch of its activity from a NO-producing enzyme to a NADPH oxidase-like system generating O2•−, thereby potentiating ROS production and oxidative stress. Moreover, in PE placentas, eNOS could be post-translationally modified by lipid peroxidation-derived aldehydes such as 4-oxononenal (ONE) a highly bioreactive agent, able to inhibit eNOS activity and NO production. This review summarizes the dysfunction of placental eNOS evoked by oxidative stress and lipid peroxidation products, and the potential consequences on PE pathogenesis.



中文翻译:

子痫前期氧化应激在胎盘内皮一氧化氮合酶功能障碍中的作用

子痫前期(PE)是一种多因素妊娠疾病,其特征是新发的妊娠高血压症伴有(或不伴有)蛋白尿或终末器官衰竭,仅在人类中观察到。它是孕产妇发病的主要原因,影响了全世界3-7%的孕妇。PE的病理生理可能是由于缺陷的滋养细胞入侵和子宫螺旋动脉重塑受损而导致的异常胎盘引起的,从而导致子宫胎盘循环的适应性较差。这将与缺氧/复氧现象,氧梯度波动,抗氧化能力改变,氧化应激和一氧化氮(NO)生物利用度降低有关。这部分是由于NO与自由基阴离子超氧化物(O 2 •-)的反应所致,后者会生成过氧亚硝酸盐ONOO-强大的促氧化剂和发炎剂。另一个机制是氧化应激对胎盘内皮一氧化氮合酶(eNOS)的逐步抑制,其通过多种事件导致eNOS解偶联例如由于增加的精氨酸酶活性而耗尽eNOS底物L-精氨酸,氧化eNOS。辅因子四氢生物蝶呤(BH4)或eNOS翻译后修饰(例如,通过S-谷胱甘肽化)。eNOS的解偶联触发其活性从产生NO的酶转变为生成O 2 •-的NADPH氧化酶样系统,从而增强ROS的产生和氧化应激。此外,在PE胎盘中,eNOS可以被脂质过氧化衍生的醛(例如4-氧合酮醛(ONE),一种高度生物活性剂)进行翻译后修饰,能够抑制eNOS活性和NO生成。这篇综述总结了氧化应激和脂质过氧化产物引起的胎盘eNOS的功能障碍,以及对PE发病机理的潜在影响。

更新日期:2021-01-19
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