Pintye Diana, Sziva Réka E, Biwer Lauren A, Karreci Esilida Sula, Jacas Sonako, Mastyugin Maxim, Török Marianna, Young Brett C, Jagtap Prakash, Southan Garry J, Jaffe Iris Z, Zsengellér Zsuzsanna K
Department of Medicine, Beth Israel Lahey Health, Boston, MA 02215, USA.
Department of Obstetrics and Gynecology, Semmelweis University, 1085 Budapest, Hungary.
Antioxidants (Basel). 2023 Nov 23;12(12):2036. doi: 10.3390/antiox12122036.
: Preeclampsia (PE) is a hypertensive disorder of pregnancy that is associated with substantial morbidity and mortality for the mother and fetus. Reduced nitric oxide bioavailability and oxidative stress contribute to the maternal and fetal pathophysiology of PE. In this study, we evaluated the efficacy of a novel dual-function nitric oxide donor/redox modulator, AKT-1005, in reducing PE symptoms in a mouse model of PE. : The potential therapeutic effect of AKT-1005 was tested in an animal model of Ad.sFlt-1-induced hypertension, proteinuria and glomerular endotheliosis, a model of PE. Pregnant Ad.sFlt-1-overexpressing CD1 mice were randomized into groups administered AKT-1005 (20 mg/kg) or a vehicle using a minipump on gd11 of pregnancy, and the impact on blood pressure and renal and placental damage were assessed. : In healthy female mice, ex vivo treatment of resistance vessels with AKT-1005 induced vasorelaxation, and 6 days of treatment in vivo did not significantly alter blood pressure with or without pregnancy. When given for 6 days during pregnancy along with Ad.sFlt-1-induced PE, AKT-1005 significantly increased plasma nitrate levels and reduced hypertension, renal endotheliosis and plasma cystatin C. In the placenta, AKT-1005 improved placental function, with reduced oxidative stress and increased endothelial angiogenesis, as measured by CD31 staining. As such, AKT-1005 treatment attenuated the Ad.sFlt-1-induced increase in placental and free plasma soluble endoglin expression. : These data suggest that AKT-1005 significantly attenuates the sFlt-1-induced PE phenotypes by inhibiting oxidative stress, the anti-angiogenic response, and increasing NO bioavailability. Additional research is warranted to investigate the role of AKT-1005 as a novel therapeutic agent for vascular disorders such as preeclampsia.
子痫前期（PE）是一种妊娠期高血压疾病，与母亲和胎儿的高发病率和死亡率相关。一氧化氮生物利用度降低和氧化应激导致了PE的母婴病理生理过程。在本研究中，我们评估了一种新型双功能一氧化氮供体/氧化还原调节剂AKT-1005在减轻PE小鼠模型中PE症状方面的疗效。：在Ad.sFlt-1诱导的高血压、蛋白尿和肾小球内皮病变的动物模型（一种PE模型）中测试了AKT-1005的潜在治疗效果。将过表达Ad.sFlt-1的怀孕CD1小鼠在妊娠第11天随机分组，使用微型泵给予AKT-1005（20mg/kg）或载体，并评估其对血压以及肾脏和胎盘损伤的影响。：在健康雌性小鼠中，用AKT-1005对阻力血管进行离体处理可诱导血管舒张，体内处理6天无论是否怀孕均未显著改变血压。在妊娠期间与Ad.sFlt-1诱导的PE一起给予6天时，AKT-1005显著提高血浆硝酸盐水平，降低高血压、肾脏内皮病变和血浆胱抑素C。在胎盘中，AKT-1005改善了胎盘功能，通过CD31染色测量，氧化应激降低，内皮血管生成增加。因此，AKT-1005治疗减弱了Ad.sFlt-1诱导的胎盘和游离血浆可溶性内皮糖蛋白表达的增加。：这些数据表明，AKT-1005通过抑制氧化应激、抗血管生成反应和增加一氧化氮生物利用度，显著减轻了sFlt-1诱导的PE表型。有必要进行进一步研究以探讨AKT-1005作为子痫前期等血管疾病新型治疗药物的作用。
