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Sapropterin reduces coronary artery malformation in offspring of pregestational diabetes mice.
Nitric Oxide ( IF 3.2 ) Pub Date : 2019-10-07 , DOI: 10.1016/j.niox.2019.10.002 Anish Engineer 1 , Yong Jin Lim 1 , Xiangru Lu 1 , Mella Y Kim 1 , Kambiz Norozi 2 , Qingping Feng 3
Nitric Oxide ( IF 3.2 ) Pub Date : 2019-10-07 , DOI: 10.1016/j.niox.2019.10.002 Anish Engineer 1 , Yong Jin Lim 1 , Xiangru Lu 1 , Mella Y Kim 1 , Kambiz Norozi 2 , Qingping Feng 3
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Endothelial nitric oxide synthase (eNOS) and oxidative stress are critical to embryonic coronary artery development. Maternal diabetes increases oxidative stress and reduces eNOS activity in the fetal heart. Sapropterin (Kuvan®) is an orally active, synthetic form of tetrahydrobiopterin (BH4) and a co-factor for eNOS with antioxidant properties. The aim of the present study was to examine the effects of sapropterin on fetal coronary artery development during pregestational diabetes in mice. Diabetes was induced by streptozotocin to adult female C57BL/6 mice. Sapropterin (10 mg/kg/day) was orally administered to pregnant mice from E0.5 to E18.5. Fetal hearts were collected at E18.5 for coronary artery morphological analysis. Sapropterin treatment to diabetic dams reduced the incidence of coronary artery malformation in offspring from 50.0% to 20.6%. Decreases in coronary artery luminal diameter, volume and abundance in fetal hearts from diabetic mothers, were prevented by sapropterin treatment. Maternal diabetes reduced epicardial epithelial-to-mesenchymal transition (EMT) and expression of transcription and growth factors critical to coronary artery development including hypoxia-inducible factor 1a (Hif1a), Snail1, Slug, β-catenin, retinaldehyde dehydrogenase 2 (Aldh1a2), basic fibroblast growth factor (bFGF) and vascular endothelial group factor receptor 2 (Vegfr2) in E12.5 hearts. Additionally, eNOS phosphorylation was lower while oxidative stress was higher in E12.5 hearts from maternal diabetes. Notably, these abnormalities were all restored to normal levels after sapropterin treatment. In conclusion, sapropterin treatment increases eNOS activity, lowers oxidative stress and reduces coronary artery malformation in offspring of pregestational diabetes. Sapropterin may have therapeutic potential in preventing coronary artery malformation in maternal diabetes.
中文翻译：
沙丙蝶呤可减少妊娠前糖尿病小鼠后代的冠状动脉畸形。
内皮一氧化氮合酶（eNOS）和氧化应激对于胚胎冠状动脉发育至关重要。母亲糖尿病会增加胎儿心脏中的氧化应激并降低 eNOS 活性。沙丙蝶呤 (Kuvan®) 是四氢生物蝶呤 (BH4) 的一种口服活性合成形式，也是具有抗氧化特性的 eNOS 辅助因子。本研究的目的是检查沙丙蝶呤对妊娠前糖尿病小鼠胎儿冠状动脉发育的影响。用链脲佐菌素诱导成年雌性 C57BL/6 小鼠患糖尿病。从 E0.5 到 E18.5，对怀孕小鼠口服沙丙蝶呤（10 mg/kg/天）。在E18.5时收集胎儿心脏用于冠状动脉形态学分析。沙丙蝶呤治疗糖尿病母鼠后，子代冠状动脉畸形的发生率从 50.0% 降低至 20.6%。沙丙蝶呤治疗可以预防糖尿病母亲的冠状动脉管腔直径、体积和胎儿心脏丰度的下降。母亲糖尿病降低了心外膜上皮间质转化 (EMT) 以及对冠状动脉发育至关重要的转录和生长因子的表达，包括缺氧诱导因子 1a (Hif1a)、Snail1、Slug、β-连环蛋白、视黄醛脱氢酶 2 (Aldh1a2)、 E12.5 心脏中的碱性成纤维细胞生长因子 (bFGF) 和血管内皮细胞群因子受体 2 (Vegfr2)。此外，在母亲患有糖尿病的 E12.5 心脏中，eNOS 磷酸化较低，而氧化应激较高。值得注意的是，沙丙蝶呤治疗后这些异常均恢复至正常水平。总之，沙丙蝶呤治疗可增加妊娠前糖尿病后代的 eNOS 活性，降低氧化应激并减少冠状动脉畸形。 沙丙蝶呤可能具有预防糖尿病孕产妇冠状动脉畸形的治疗潜力。
更新日期：2019-10-07
中文翻译：
沙丙蝶呤可减少妊娠前糖尿病小鼠后代的冠状动脉畸形。
内皮一氧化氮合酶（eNOS）和氧化应激对于胚胎冠状动脉发育至关重要。母亲糖尿病会增加胎儿心脏中的氧化应激并降低 eNOS 活性。沙丙蝶呤 (Kuvan®) 是四氢生物蝶呤 (BH4) 的一种口服活性合成形式，也是具有抗氧化特性的 eNOS 辅助因子。本研究的目的是检查沙丙蝶呤对妊娠前糖尿病小鼠胎儿冠状动脉发育的影响。用链脲佐菌素诱导成年雌性 C57BL/6 小鼠患糖尿病。从 E0.5 到 E18.5，对怀孕小鼠口服沙丙蝶呤（10 mg/kg/天）。在E18.5时收集胎儿心脏用于冠状动脉形态学分析。沙丙蝶呤治疗糖尿病母鼠后，子代冠状动脉畸形的发生率从 50.0% 降低至 20.6%。沙丙蝶呤治疗可以预防糖尿病母亲的冠状动脉管腔直径、体积和胎儿心脏丰度的下降。母亲糖尿病降低了心外膜上皮间质转化 (EMT) 以及对冠状动脉发育至关重要的转录和生长因子的表达，包括缺氧诱导因子 1a (Hif1a)、Snail1、Slug、β-连环蛋白、视黄醛脱氢酶 2 (Aldh1a2)、 E12.5 心脏中的碱性成纤维细胞生长因子 (bFGF) 和血管内皮细胞群因子受体 2 (Vegfr2)。此外，在母亲患有糖尿病的 E12.5 心脏中，eNOS 磷酸化较低，而氧化应激较高。值得注意的是，沙丙蝶呤治疗后这些异常均恢复至正常水平。总之，沙丙蝶呤治疗可增加妊娠前糖尿病后代的 eNOS 活性，降低氧化应激并减少冠状动脉畸形。 沙丙蝶呤可能具有预防糖尿病孕产妇冠状动脉畸形的治疗潜力。
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