Oregon Health and Science University, Portland, OR, USA.
FASEB J. 2012 Jan;26(1):397-408. doi: 10.1096/fj.10-179895. Epub 2011 Oct 5.
Tri-iodo-l-thyronine (T(3)) suppresses the proliferation of near-term serum-stimulated fetal ovine cardiomyocytes in vitro. Thus, we hypothesized that T(3) is a major stimulant of cardiomyocyte maturation in vivo. We studied 3 groups of sheep fetuses on gestational days 125-130 (term ∼145 d): a T(3)-infusion group, to mimic fetal term levels (plasma T(3) levels increased from ∼0.1 to ∼1.0 ng/ml; t(1/2)∼24 h); a thyroidectomized group, to produce low thyroid hormone levels; and a vehicle-infusion group, to serve as intact controls. At 130 d of gestation, sections of left ventricular freewall were harvested, and the remaining myocardium was enzymatically dissociated. Proteins involved in cell cycle regulation (p21, cyclin D1), proliferation (ERK), and hypertrophy (mTOR) were measured in left ventricular tissue. Evidence that elevated T(3) augmented the maturation rate of cardiomyocytes included 14% increased width, 31% increase in binucleation, 39% reduction in proliferation, 150% reduction in cyclin D1 protein, and 500% increase in p21 protein. Increased expression of phospho-mTOR, ANP, and SERCA2a also suggests that T(3) promotes maturation and hypertrophy of fetal cardiomyocytes. Thyroidectomized fetuses had reduced cell cycle activity and binucleation. These findings support the hypothesis that T(3) is a prime driver of prenatal cardiomyocyte maturation.
三碘甲状腺原氨酸（T3）抑制体外近期血清刺激的胎儿绵羊心肌细胞的增殖。因此，我们假设 T3 是体内心肌细胞成熟的主要刺激物。我们研究了妊娠第 125-130 天（足月约 145 天）的 3 组绵羊胎儿：T3 输注组，模拟胎儿足月水平（血浆 T3 水平从约 0.1 增加到约 1.0ng/ml；t1/2 约 24 小时）；甲状腺切除术组，产生低甲状腺激素水平；和载体输注组，作为完整对照。在妊娠第 130 天，取左心室游离壁的切片，并从剩余的心肌中酶解。在左心室组织中测量细胞周期调节蛋白（p21、细胞周期蛋白 D1）、增殖（ERK）和肥大（mTOR）的蛋白质。升高的 T3 增加心肌细胞成熟率的证据包括宽度增加 14%、双核化增加 31%、增殖减少 39%、细胞周期蛋白 D1 蛋白减少 150%和 p21 蛋白增加 500%。磷酸化 mTOR、ANP 和 SERCA2a 的表达增加也表明 T3 促进胎儿心肌细胞的成熟和肥大。甲状腺切除胎儿的细胞周期活性和双核化减少。这些发现支持 T3 是产前心肌细胞成熟的主要驱动因素的假设。
