Abstract

Exposure to adverse factors in utero may lead to adaptive changes in cardiac structure and metabolism, which increases the risk of chronic cardiovascular disease later in life. Studies showed that the angiotensin II type 1 receptor autoantibodies (AT1-AAs) are able to cross the placenta into the circulation of pregnant rodents’ embryo, which adversely affects embryogenesis. However, the effects of AT1-AA exposure on the fetal heart in utero are still unknown. In this study, we investigated whether intrauterine AT1-AA exposure has adverse effects on fetal heart structure, function and metabolism. AT1-AA-positive pregnant mouse models were successfully established by passive immunity, evidenced by increased AT1-AA content. Morphological and ultrasonic results showed that the fetal mice on embryonic day 18 (E18) of AT1-AA group have loose and disordered myocardial structure, and decreased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), compared with control groups. The myocardium of AT1-AA group fetal mice on E18 exhibited increased expression of the key molecules in the glycolytic pathway, pyruvate and lactic acid content and ATP production, suggesting that the glycolysis rate was enhanced. Furthermore, the enhanced effect of glycolysis caused by AT1-AA is mainly through the PPARβ/δ pathway. These data confirmed that fetus exposure to AT1-AA in utero developed left ventricular dysfunction, myocardial structural arrangement disorders, and enhanced glycolysis on E18. Our results support AT1-AA being a potentially harmful factor for cardiovascular disease in fetal mice.

中文翻译：

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子宫内AT1受体自身抗体暴露导致胎儿小鼠心脏功能障碍和糖酵解增加

摘要

子宫内暴露于不利因素可能会导致心脏结构和新陈代谢的适应性变化，从而增加生命后期罹患慢性心血管疾病的风险。研究表明，血管紧张素II 1型受体自身抗体（AT1-AAs）能够穿过胎盘进入怀孕啮齿动物胚胎的循环中，从而对胚胎发生产生不利影响。然而，AT1-AA暴露对子宫内胎儿心脏的影响仍然未知。在这项研究中，我们调查了宫内AT1-AA暴露是否对胎儿心脏结构，功能和代谢产生不利影响。AT1-AA阳性的怀孕小鼠模型通过被动免疫成功建立，其证据是AT1-AA含量增加。形态学和超声结果显示，与对照组相比，AT1-AA组在胚胎第18天（E18）的小鼠的心肌结构疏松且紊乱，左室射血分数（LVEF）和左室分数缩短（LVFS）降低。AT1-AA组胎鼠在E18上的心肌表现出关键分子在糖酵解途径中的表达增加，丙酮酸和乳酸含量以及ATP的产生，表明糖酵解速率提高了。此外，AT1-AA引起的糖酵解作用增强主要是通过PPARβ/δ途径。这些数据证实胎儿暴露于AT1-AA子宫内的患者发展为左心功能不全，心肌结构排列异常，并在E18上糖酵解增强。我们的结果支持AT1-AA是胎鼠心血管疾病的潜在有害因素。