Department of Pharmacology, Key Laboratory of Molecular Target & Clinical Pharmacology, School of, Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Guangzhou Institute of Cardiovascular Disease, Guangzhou Key Laboratory of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
J Endocrinol. 2021 Jun 16;250(1):1-12. doi: 10.1530/JOE-20-0562.
Our previous study has demonstrated maternal high-fat diet (HFD) caused sex-dependent cardiac hypertrophy in adult male, but not female offspring. The present study tested the hypothesis that estrogen normalizes maternal HFD-induced cardiac hypertrophy by regulating angiotensin II receptor (ATR) expression in adult female offspring. Pregnant rats were divided into the normal diet (ND) and HFD (60% kcal fat) groups. Ovariectomy (OVX) and 17β-estradiol (E2) replacement were performed on 8-week-old female offspring. Maternal HFD had no effect on left ventricular (LV) wall thickness, cardiac function and molecular markers of cardiac hypertrophy function in sham groups. However, maternal HFD caused cardiac hypertrophy of offspring in OVX groups, which was abrogated by E2 replacement. In addition, maternal HFD had no effect on ERα and ERβ in sham groups. In contrast, HFD significantly decreased ERα, but not ERβ in OVX groups. In sham groups, there was no difference in the cardiac ATR type 1 (AT1R) and ATR type 2 (AT2R) between ND and HFD offspring. HFD significantly increased AT2R, but not AT1R in OVX groups. Furthermore, maternal HFD resulted in decreased glucocorticoid receptors (GRs) binding to the glucocorticoid response elements at the AT2R promoter, which was due to decreased GRs in hearts from OVX offspring. These HFD-induced changes in OVX groups were abrogated by E2 replacement. These results support a key role of estrogen in the sex difference of maternal HFD-induced cardiac hypertrophy in offspring, and suggest that estrogen protects female offspring from cardiac hypertrophy in adulthood by regulating AT2R.
我们之前的研究表明，母体高脂肪饮食（HFD）会导致成年雄性后代出现性别依赖性心肌肥厚，但不会导致雌性后代出现这种情况。本研究旨在验证以下假设，即雌激素通过调节成年雌性后代的血管紧张素 II 受体（ATR）表达来使母体 HFD 诱导的心肌肥厚恢复正常。将怀孕的大鼠分为正常饮食（ND）和 HFD（60%卡路里脂肪）组。对 8 周龄的雌性后代进行卵巢切除术（OVX）和 17β-雌二醇（E2）替换。在假手术组中，母体 HFD 对左心室（LV）壁厚度、心脏功能和心肌肥厚功能的分子标志物没有影响。然而，在 OVX 组中，母体 HFD 导致了后代的心肌肥厚，而 E2 替换则消除了这种影响。此外，在假手术组中，母体 HFD 对 ERα 和 ERβ 没有影响。相比之下，HFD 显著降低了 OVX 组中的 ERα，但没有降低 ERβ。在假手术组中，ND 和 HFD 后代之间的心脏 ATR 类型 1（AT1R）和 ATR 类型 2（AT2R）没有差异。HFD 显著增加了 OVX 组中的 AT2R，但没有增加 AT1R。此外，母体 HFD 导致 AT2R 启动子上的糖皮质激素受体（GRs）与糖皮质激素反应元件的结合减少，这是由于 OVX 后代心脏中的 GRs 减少所致。E2 替换消除了 OVX 组中这些由 HFD 引起的变化。这些结果支持雌激素在母体 HFD 诱导的后代心肌肥厚的性别差异中的关键作用，并表明雌激素通过调节 AT2R 来保护雌性后代在成年期免受心肌肥厚的影响。
