Cardiovascular Center, Children's Hospital of Fudan University, Shanghai, China; MOH Key Laboratory of Neonatal Diseases at Children's Hospital, Fudan University, Shanghai, China.
Ultrasound Department, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
Biomed Pharmacother. 2021 Jan;133:110989. doi: 10.1016/j.biopha.2020.110989. Epub 2020 Dec 8.
Maternal obesity induces adverse cardiac programming in offspring, and effective interventions are needed to prevent cardiovascular ill-health. Herein we hypothesized that exposure to maternal obesogenic diet-induced obesity in mice results in left ventricular remodelling and hypertrophy in early childhood, and that maternal N-acetylcysteine (NAC) treatment alleviates these effects in a sex-dependent manner.
The maternal obesity was induced in mice by the consumption of a Western diet accompanied by a 20 % sucrose solution. To determine the effect of NAC on the cardiac outcomes induced by maternal obesity, obese dams were continuously exposed to the obesogenic diet, with or without the oral NAC treatment during pregnancy. Left ventricular remodelling and hypertrophy occurred as early as 7 days after birth in the male offspring of obese dams (O-OB) compared with controls (O-CO). An over-expression of key genes and markers related to cardiac fibrosis accompanied by more disorganized myofibrils was observed in the hearts of neonatal male O-OB mice. When we next evaluated the level of oxidative stress in the hearts of neonatal mice, the activity of enzymatic antioxidants declined and expression of NOX enzyme complex was up-regulated in O-OB offspring hearts, but was normal in the offspring of NAC treated mice (O-OB/NAC). Maternal obesity also activated cardiac Akt and mammalian target of rapamycin (mTOR) signalling in offspring, and NAC treatment restored offspring cardiac Akt-mTOR signalling to normal irrespective of sex. NAC treatment did not prevent cardiomyocyte hypertrophy but did alleviate increased heart weight, interventricular septal thickness, and collagen content in male O-OB/NAC pups.
Collectively, our results indicated that NAC blunted cardiac fibrosis and related ventricular hypertrophy of male neonatal offspring in the setting of maternal obesity, potentially acting by reducing oxidative stress. The present study provides a basis for investigating the role of NAC in nutrition-related cardiac programming.
母体肥胖会导致后代心脏发育不良，需要有效的干预措施来预防心血管疾病。在此，我们假设，在小鼠中暴露于母体肥胖诱导的饮食诱导肥胖会导致幼年期左心室重构和肥大，并且母体 N-乙酰半胱氨酸 (NAC) 治疗以性别依赖的方式缓解这些影响。
通过给母鼠喂食西方饮食并同时摄入 20%的蔗糖溶液来诱导母体肥胖。为了确定 NAC 对母体肥胖引起的心脏结果的影响，肥胖母鼠在怀孕期间持续暴露于致肥胖饮食中，同时或不接受口服 NAC 治疗。与对照组 (O-CO) 相比，肥胖母鼠 (O-OB) 的雄性后代在出生后 7 天就出现左心室重构和肥大。在新生雄性 O-OB 小鼠的心脏中观察到关键基因和与心脏纤维化相关的标志物的过度表达，伴随着肌原纤维更紊乱。当我们接下来评估新生小鼠心脏中的氧化应激水平时，发现 O-OB 后代心脏中的酶抗氧化剂活性下降，NOX 酶复合物的表达上调，但 NAC 处理的小鼠 (O-OB/NAC) 后代的心脏则正常。母体肥胖还激活了后代心脏中的 Akt 和哺乳动物雷帕霉素靶蛋白 (mTOR) 信号通路，而 NAC 治疗无论性别如何，均使后代心脏 Akt-mTOR 信号通路恢复正常。NAC 治疗不能预防心肌细胞肥大，但可以减轻雄性 O-OB/NAC 幼仔的心脏重量、室间隔厚度和胶原含量的增加。
总之，我们的结果表明，NAC 减轻了母体肥胖小鼠雄性新生儿后代的心脏纤维化和相关心室肥大，可能通过降低氧化应激起作用。本研究为研究 NAC 在营养相关心脏编程中的作用提供了基础。
