PDF(Pubmed)
Abstract：
Maternal hypothyroidism (MH) could adversely affect the cardiac disease responses of the progeny. This study tested the hypothesis that MH reduces early postnatal cardiomyocyte (CM) proliferation so that the adult heart of MH progeny has a smaller number of larger cardiac myocytes, which imparts adverse cardiac disease responses following injury. Thyroidectomy (TX) was used to establish MH. The progeny from mice that underwent sham or TX surgery were termed Ctrl (control) or MH (maternal hypothyroidism) progeny, respectively. MH progeny had similar heart weight (HW) to body weight (BW) ratios and larger CM size consistent with fewer CMs at postnatal day 60 (P60) compared with Ctrl (control) progeny. MH progeny had lower numbers of EdU+, Ki67+, and phosphorylated histone H3 (PH3)+ CMs, which suggests they had a decreased CM proliferation in the postnatal timeframe. RNA-seq data showed that genes related to DNA replication were downregulated in P5 MH hearts, including bone morphogenetic protein 10 (Bmp10). Both in vivo and in vitro studies showed Bmp10 treatment increased CM proliferation. After transverse aortic constriction (TAC), the MH progeny had more severe cardiac pathological remodeling compared with the Ctrl progeny. Thyroid hormone (T4) treatment for MH mothers preserved their progeny\'s postnatal CM proliferation capacity and prevented excessive pathological remodeling after TAC. Our results suggest that CM proliferation during early postnatal development was significantly reduced in MH progeny, resulting in fewer CMs with hypertrophy in adulthood. These changes were associated with more severe cardiac disease responses after pressure overload.NEW & NOTEWORTHY Our study shows that compared with Ctrl (control) progeny, the adult progeny of mothers who have MH (MH progeny) had fewer CMs. This reduction of CM numbers was associated with decreased postnatal CM proliferation. Gene expression studies showed a reduced expression of Bmp10 in MH progeny. Bmp10 has been linked to myocyte proliferation. In vivo and in vitro studies showed that Bmp10 treatment of MH progeny and their myocytes could increase CM proliferation. Differences in CM number and size in adult hearts of MH progeny were linked to more severe cardiac structural and functional remodeling after pressure overload. T4 (synthetic thyroxine) treatment of MH mothers during their pregnancy, prevented the reduction in CM number in their progeny and the adverse response to disease stress.
摘要：
目的：母体甲状腺功能减退症（MH）可能对子代的心脏疾病反应产生不利影响。这项研究检验了以下假设：MH减少了出生后早期心肌细胞（CM）的增殖，从而使MH后代的成年心脏具有较少数量的较大心肌细胞，在受伤后引起不良的心脏病反应。
结果：使用甲状腺切除术（TX）建立MH。接受Sham或TX手术的小鼠的后代称为Ctrl（对照）或MH（母体甲状腺功能减退）后代，分别。与Ctrl后代相比，MH后代的心脏重量（HW）与体重（BW）之比相似，CM大小更大，出生后第60天（P60）的CM较少。MH后代的EdU+数量较低，Ki67+,和PH3+CM，这表明他们在出生后的时间段内CM增殖减少。RNA-seq数据显示，与DNA复制相关的基因在P5MH心脏中下调，包括骨形态发生蛋白10(Bmp10)。体内和体外研究均显示Bmp10处理增加CM增殖。横向主动脉缩窄(TAC)后,与Ctrl子代相比，MH子代的心脏病理重塑更严重。MH母亲的甲状腺激素（T4）治疗保留了后代的出生后CM增殖能力，并防止了TAC后过度的病理性重塑。
结论：我们的结果表明，在MH后代中，出生后早期发育过程中的CM增殖明显减少，导致成年期肥大的CM减少。这些变化与压力超负荷后更严重的心脏病反应有关。
结果：使用甲状腺切除术（TX）建立MH。接受Sham或TX手术的小鼠的后代称为Ctrl（对照）或MH（母体甲状腺功能减退）后代，分别。与Ctrl后代相比，MH后代的心脏重量（HW）与体重（BW）之比相似，CM大小更大，出生后第60天（P60）的CM较少。MH后代的EdU+数量较低，Ki67+,和PH3+CM，这表明他们在出生后的时间段内CM增殖减少。RNA-seq数据显示，与DNA复制相关的基因在P5MH心脏中下调，包括骨形态发生蛋白10(Bmp10)。体内和体外研究均显示Bmp10处理增加CM增殖。横向主动脉缩窄(TAC)后,与Ctrl子代相比，MH子代的心脏病理重塑更严重。MH母亲的甲状腺激素（T4）治疗保留了后代的出生后CM增殖能力，并防止了TAC后过度的病理性重塑。
结论：我们的结果表明，在MH后代中，出生后早期发育过程中的CM增殖明显减少，导致成年期肥大的CM减少。这些变化与压力超负荷后更严重的心脏病反应有关。
