Zou Jianqiu, Ma Wenxia, Littlejohn Rodney, Li Jie, Stansfield Brian K, Kim Il-Man, Liu Jinbao, Zhou Jiliang, Weintraub Neal L, Su Huabo
Vascular Biology Center, Medical College of Georgia, Augusta University , Augusta, Georgia.
Department of Pediatrics, Medical College of Georgia, Augusta University , Augusta, Georgia.
Am J Physiol Heart Circ Physiol. 2019 Jun 1;316(6):H1406-H1416. doi: 10.1152/ajpheart.00806.2018. Epub 2019 Mar 29.
Alterations in perinatal conditions (such as preterm birth) is linked to adult health and disease, in particular, the cardiovascular system. Neddylation, a novel posttranslational modification through which the ubiquitin-like protein NEDD8 is conjugated to protein substrates, has emerged as an important mechanism regulating embryonic cardiac chamber maturation. However, the importance of neddylation in postpartum cardiac development has not been investigated. Here, we aimed to determine whether transient, postnatal inhibition of neddylation has immediate and prolonged impact on the structure and function of the neonatal and adult hearts. Sprague-Dawley pups were given three intraperitoneal injections of MLN4924 (MLN), a specific neddylation inhibitor, at postnatal days (P)1, 3, and 5. Cardiac structure and function were temporally assessed during aging and after 2 wk of isoproterenol (ISO) infusion in adulthood. MLN treatment resulted in modest reduction of neddylated proteins in neonatal hearts. The MLN-treated rats developed cardiac hypertrophy and dysfunction by P7, which was accompanied by significantly reduced cardiomyocyte proliferation. At 3 mo of age, cardiac contractile function was restored in MLN-treated rats, but MLN-treated hearts displayed hypertrophic phenotype. Whereas ISO infusion triggered compensatory cardiac hypertrophy without impairing cardiac contractility in the control rats, the MLN-treated rats displayed a similar degree of hypertrophy, which quickly progressed to decompensation with ventricular wall thinning, chamber dilatation, and reduced ejection fraction as well as exacerbated pathological cardiac remodeling. Our findings suggest that neddylation is required for postnatal cardiac development and that perturbation of neddylation during development predisposes adult hearts to cardiac failure under stress conditions. Our study demonstrates that perinatal perturbation of neddylation induces cardiomyopathy, impairs postnatal cardiac development, and increases susceptibility to catecholamine-induced cardiac dysfunction. The results reveal a previously unappreciated role of neddylation in postnatal cardiac maturation and call for close monitoring for the potential cardiotoxicity of MLN4924 (pevonedistat) and other agents that modify neddylation, especially in pregnant women and preadolescents.
围产期状况的改变（如早产）与成人健康及疾病相关，尤其是心血管系统疾病。Neddylation是一种新的翻译后修饰，通过泛素样蛋白NEDD8与蛋白质底物结合来实现，它已成为调节胚胎心脏腔室成熟的重要机制。然而，Neddylation在产后心脏发育中的重要性尚未得到研究。在此，我们旨在确定产后短暂抑制Neddylation是否会对新生和成年心脏的结构与功能产生即时和长期影响。在出生后第1、3和5天，给Sprague-Dawley幼崽腹腔注射三次特异性Neddylation抑制剂MLN4924（MLN）。在衰老过程中以及成年后异丙肾上腺素（ISO）输注2周后，对心脏结构和功能进行定期评估。MLN处理导致新生心脏中Neddylated蛋白适度减少。经MLN处理的大鼠在出生后第7天出现心脏肥大和功能障碍，同时伴有心肌细胞增殖显著减少。在3月龄时，经MLN处理的大鼠心脏收缩功能恢复，但经MLN处理的心脏呈现肥大表型。在对照大鼠中，ISO输注引发代偿性心脏肥大且不损害心脏收缩力，而经MLN处理的大鼠表现出相似程度的肥大，随后迅速发展为失代偿，出现心室壁变薄、心腔扩张、射血分数降低以及病理性心脏重塑加剧。我们的研究结果表明，Neddylation是产后心脏发育所必需的，发育过程中Neddylation的扰动会使成年心脏在应激条件下易患心力衰竭。我们的研究表明，围产期Neddylation的扰动会诱发心肌病，损害产后心脏发育，并增加对儿茶酚胺诱导的心脏功能障碍的易感性。这些结果揭示了Neddylation在产后心脏成熟中以前未被认识的作用，并呼吁密切监测MLN4924（pevonedistat）和其他改变Neddylation的药物的潜在心脏毒性，尤其是在孕妇和青春期前儿童中。
