Sapropterin Treatment Prevents Congenital Heart Defects Induced by Pregestational Diabetes Mellitus in Mice
Sapropterin Treatment Prevents Congenital Heart Defects Induced by Pregestational Diabetes Mellitus in Mice
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DOI：
10.1161/jaha.118.009624
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发表时间：
2018-11-06
影响因子：
5.4
通讯作者：
Feng, Qingping
中科院分区：
文献类型：
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作者：
Engineer, Anish;Saiyin, Tana;Feng, Qingping
背景-四氢生物蝶呤是内皮型一氧化氮合酶（eNOS）的辅因子，eNOS对胚胎心脏发育至关重要。我们的目的是研究沙丙蝶呤（Kuvan），一种口服活性合成形式的四氢生物蝶呤对eNOS解偶联和先天性心脏病（CHD）引起的妊娠前糖尿病在mice.Methods和Results-Adult雌性小鼠诱导妊娠前糖尿病链脲佐菌素和繁殖正常雄性小鼠产生后代。妊娠小鼠在妊娠期间用沙丙蝶呤或溶剂处理。通过组织学分析确定CHD。细胞增殖，eNOS二聚化和活性氧的生产进行了评估，在胎儿心脏。妊娠前糖尿病可导致其后代发生一系列CHD。在糖尿病母鼠中口服沙丙蝶呤可显著降低CHD的发生率，从59%降至27%，沙丙蝶呤治疗组中不存在主要异常，如房室间隔缺损和右心室双出口。谱系追踪显示，妊娠前糖尿病导致第二心脏领域的祖细胞减少承诺的流出道，内膜垫，心室心肌的胎儿心脏。值得注意的是，降低的细胞增殖和心脏转录因子表达诱导的母体糖尿病与沙丙蝶呤治疗正常化。此外，沙丙蝶呤给药的糖尿病母鼠增加eNOS二聚化和降低活性氧水平在胎儿heart. Conclusions沙丙蝶呤治疗糖尿病母亲改善eNOS耦合，增加细胞增殖，并防止发展中的先天性心脏病的后代。因此，沙丙蝶呤可能具有预防妊娠前糖尿病CHD的治疗潜力。
Background-Tetrahydrobiopterin is a cofactor of endothelial NO synthase (eNOS), which is critical to embryonic heart development. We aimed to study the effects of sapropterin (Kuvan), an orally active synthetic form of tetrahydrobiopterin on eNOS uncoupling and congenital heart defects (CHDs) induced by pregestational diabetes mellitus in mice.Methods and Results-Adult female mice were induced to pregestational diabetes mellitus by streptozotocin and bred with normal male mice to produce offspring. Pregnant mice were treated with sapropterin or vehicle during gestation. CHDs were identified by histological analysis. Cell proliferation, eNOS dimerization, and reactive oxygen species production were assessed in the fetal heart. Pregestational diabetes mellitus results in a spectrum of CHDs in their offspring. Oral treatment with sapropterin in the diabetic dams significantly decreased the incidence of CHDs from 59% to 27%, and major abnormalities, such as atrioventricular septal defect and double-outlet right ventricle, were absent in the sapropterin-treated group. Lineage tracing reveals that pregestational diabetes mellitus results in decreased commitment of second heart field progenitors to the outflow tract, endocardial cushions, and ventricular myocardium of the fetal heart. Notably, decreased cell proliferation and cardiac transcription factor expression induced by maternal diabetes mellitus were normalized with sapropterin treatment. Furthermore, sapropterin administration in the diabetic dams increased eNOS dimerization and lowered reactive oxygen species levels in the fetal heart.Conclusions-Sapropterin treatment in the diabetic mothers improves eNOS coupling, increases cell proliferation, and prevents the development of CHDs in the offspring. Thus, sapropterin may have therapeutic potential in preventing CHDs in pregestational diabetes mellitus.