Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, No.115, Nanjing Road, HePing District, Shenyang, 110001, China.
Department of Cardiovascular Ultrasound, General Hospital of Northern Theater Command, Shenyang, China.
BMC Cardiovasc Disord. 2020 Aug 14;20(1):369. doi: 10.1186/s12872-020-01646-3.
It is unclear whether the offspring of subclinical hypothyroidism (SCH) pregnant rats still have abnormal cardiac development, and whether early intervention with L-T4 can improve the abnormality of these offspring. Therefore, the aim of this study was to investigate the effect of early L-T4 intervention on the heart development of offspring of SCH pregnant rats and its possible molecular mechanism.
Eighty female Wistar rats were randomly divided into Sham group (placebo control), SCH group, LT4-E10 group (L-T4 treatment started on the 10th day of gestation), and LT4-E13 group (L-T4 treatment started on the 13th day of gestation). Each group was further divided into E16 (16th day of gestation), E18 (18th day of gestation), P5 (5th day postnatal day), and P10 (10th day postnatal day) subgroups. The levels of serum TT4 and TSH, the ratio of heart weight to body weight of offspring rats, the expression of metabolic enzymes, and the histopathology of cardiomyocytes were determined. To elucidate the effects of L-T4 on cardiac development of offspring of SCH pregnant rats, the expression levels of GATA4, Nkx2-5 and proteins involved in BMP4/Smad4 signaling pathway were detected by immunohistochemistry, real time quantitative polymerase chain reaction and Western blotting to elucidate the molecular mechanism of L-T4 regulating the heart development of the offspring of SCH pregnant rats.
Compared with Sham group, serum TSH was significantly increased in SCH pregnant rats. Moreover, early L-T4 intervention significantly reduced the levels of serum TSH. Compared with the offspring in the SCH group, early L-T4 intervention significantly increased the heart weight, heart weight to body weight ratio, the activities of succinate dehydrogenase (SDH), Na/K-ATPase and Ca-ATPase, but reduced myocardial cell shrinkage and nuclear staining, hyperemia/congestion and vacuolar degeneration. In addition, early L-T4 intervention not only significantly increased the mRNA and protein expression of Gata4 and Nkx2-5, but also increased the protein expression involved in BMP4/Smad4 signal pathway in myocardium of the offspring of SCH pregnant rats.
Early L-T4 intervention can regulate the cardiac development of the offspring of SCH pregnant rats by activating BMP4/Smad4 signaling pathway and increasing the expression of Gata4 and Nkx2-5 proteins.
尚不清楚亚临床甲状腺功能减退症（SCH）孕鼠的后代心脏发育是否仍存在异常，以及早期给予 L-T4 干预是否能改善这些后代的异常。因此，本研究旨在探讨早期 L-T4 干预对 SCH 孕鼠后代心脏发育的影响及其可能的分子机制。
80 只雌性 Wistar 大鼠随机分为假手术组（安慰剂对照）、SCH 组、LT4-E10 组（妊娠第 10 天开始 L-T4 治疗）和 LT4-E13 组（妊娠第 13 天开始 L-T4 治疗）。每组进一步分为 E16（妊娠第 16 天）、E18（妊娠第 18 天）、P5（生后第 5 天）和 P10（生后第 10 天）亚组。测定血清 TT4 和 TSH 水平、仔鼠心脏重量与体重比、代谢酶表达及心肌细胞组织病理学。为阐明 L-T4 对 SCH 孕鼠后代心脏发育的影响，采用免疫组化、实时定量聚合酶链反应和 Western 印迹法检测 GATA4、Nkx2-5 及 BMP4/Smad4 信号通路相关蛋白的表达水平，以阐明 L-T4 调节 SCH 孕鼠后代心脏发育的分子机制。
与假手术组相比，SCH 孕鼠血清 TSH 显著升高，且早期 L-T4 干预可显著降低血清 TSH 水平。与 SCH 组仔鼠相比，早期 L-T4 干预可显著增加心脏重量、心脏重量与体重比，同时增加琥珀酸脱氢酶（SDH）、Na/K-ATP 酶和 Ca-ATP 酶的活性，减少心肌细胞皱缩和核染色、充血/淤血和空泡变性。此外，早期 L-T4 干预不仅显著增加 SCH 孕鼠后代心肌中 Gata4 和 Nkx2-5 的 mRNA 和蛋白表达，还增加了 BMP4/Smad4 信号通路相关蛋白的表达。
早期 L-T4 干预可通过激活 BMP4/Smad4 信号通路和增加 Gata4 和 Nkx2-5 蛋白的表达来调节 SCH 孕鼠后代的心脏发育。
