Hennig Maria, Fiedler Saskia, Jux Christian, Thierfelder Ludwig, Drenckhahn Jörg-Detlef
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Department of Pediatric Cardiology, University Hospital Münster, Münster, Germany.
J Am Heart Assoc. 2017 Aug 4;6(8):e005506. doi: 10.1161/JAHA.117.005506.
Fetal growth impacts cardiovascular health throughout postnatal life in humans. Various animal models of intrauterine growth restriction exhibit reduced heart size at birth, which negatively influences cardiac function in adulthood. The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and growth factor availability with cell growth, thereby regulating organ size. This study aimed at elucidating a possible involvement of mTORC1 in intrauterine growth restriction and prenatal heart growth.
We inhibited mTORC1 in fetal mice by rapamycin treatment of pregnant dams in late gestation. Prenatal rapamycin treatment reduces mTORC1 activity in various organs at birth, which is fully restored by postnatal day 3. Rapamycin-treated neonates exhibit a 16% reduction in body weight compared with vehicle-treated controls. Heart weight decreases by 35%, resulting in a significantly reduced heart weight/body weight ratio, smaller left ventricular dimensions, and reduced cardiac output in rapamycin- versus vehicle-treated mice at birth. Although proliferation rates in neonatal rapamycin-treated hearts are unaffected, cardiomyocyte size is reduced, and apoptosis increased compared with vehicle-treated neonates. Rapamycin-treated mice exhibit postnatal catch-up growth, but body weight and left ventricular mass remain reduced in adulthood. Prenatal mTORC1 inhibition causes a reduction in cardiomyocyte number in adult hearts compared with controls, which is partially compensated for by an increased cardiomyocyte volume, resulting in normal cardiac function without maladaptive left ventricular remodeling.
Prenatal rapamycin treatment of pregnant dams represents a new mouse model of intrauterine growth restriction and identifies an important role of mTORC1 in perinatal cardiac growth.
胎儿生长会影响人类出生后一生的心血管健康。各种子宫内生长受限的动物模型在出生时心脏大小减小，这对成年后的心脏功能产生负面影响。雷帕霉素复合物1（mTORC1）将营养物质和生长因子的可用性与细胞生长整合在一起，从而调节器官大小。本研究旨在阐明mTORC1在子宫内生长受限和产前心脏生长中可能的作用。
我们在妊娠晚期通过对怀孕母鼠进行雷帕霉素治疗来抑制胎儿小鼠体内的mTORC1。产前雷帕霉素治疗可降低出生时各器官中的mTORC1活性，到出生后第3天该活性完全恢复。与接受载体治疗的对照组相比，接受雷帕霉素治疗的新生儿体重降低了16%。心脏重量减少35%，导致雷帕霉素治疗组与载体治疗组小鼠在出生时心脏重量/体重比显著降低、左心室尺寸减小以及心输出量减少。虽然接受雷帕霉素治疗的新生小鼠心脏中的增殖率未受影响，但与接受载体治疗的新生儿相比，心肌细胞大小减小且细胞凋亡增加。接受雷帕霉素治疗的小鼠出生后会出现追赶生长，但成年后体重和左心室质量仍降低。与对照组相比，产前mTORC1抑制导致成年心脏中的心肌细胞数量减少，这部分地通过心肌细胞体积增加得到补偿，从而在没有适应性不良的左心室重塑的情况下实现正常心脏功能。
对怀孕母鼠进行产前雷帕霉素治疗代表了一种子宫内生长受限的新小鼠模型，并确定了mTORC1在围产期心脏生长中的重要作用。
