Effects of maternal hypothyroidism on postnatal cardiomyocyte proliferation and cardiac disease responses of the progeny

Abstract

Objective: 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. Methods and Results: 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 progeny. MH progeny had lower numbers of EdU+, Ki67+, and 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. Conclusions: 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.

HDAC1/2/3‐mediated downregulation of neurogranin is involved in cognitive impairment in offspring exposed to maternal subclinical hypothyroidism

“…The period of pregnancy is a crucial timeframe during which fetal development occurs. Various maternal circumstances might modify the levels of nutrients and hormones in circulation, potentially influencing the long‐term health of offspring 9–14 . Maternal thyroid hormones are crucial for the process of brain development, metabolic regulation, cardiovascular function, as well as normal growth and maturation of bones 14–18 .…”

“…Various maternal circumstances might modify the levels of nutrients and hormones in circulation, potentially influencing the long-term health of offspring. [9][10][11][12][13][14] Maternal thyroid hormones are crucial for the process of brain development, metabolic regulation, cardiovascular function, as well as normal growth and maturation of bones. [14][15][16][17][18] Profound consequences on the health of the offspring arise from a complete dependence of the fetus on maternal thyroid hormones until the second trimester of pregnancy in humans and mid-gestation in mice, and sustained influence of maternal thyroid hormones at later stages.…”

“…[9][10][11][12][13][14] Maternal thyroid hormones are crucial for the process of brain development, metabolic regulation, cardiovascular function, as well as normal growth and maturation of bones. [14][15][16][17][18] Profound consequences on the health of the offspring arise from a complete dependence of the fetus on maternal thyroid hormones until the second trimester of pregnancy in humans and mid-gestation in mice, and sustained influence of maternal thyroid hormones at later stages. 19,20 Accumulating evidence from humans and other mammals indicates that maternal serious thyroid hormone deficiencies (e.g., maternal hypothyroidism) can be hazardous for the future cognitive performance of the offspring, such as cretinism and mental retardation.…”