Olson Aaron K, Protheroe Kristen N, Scholz Thomas D, Segar Jeffrey L
Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
J Soc Gynecol Investig. 2006 Apr;13(3):157-65. doi: 10.1016/j.jsgi.2006.01.004.
Protein kinase B (Akt) and the mitogen-activated protein kinases (MAPKs) mediate hypertrophy in the adult heart, although their importance in the developing heart is poorly understood. The goal of the current study was to determine if volume loading the fetal heart resulting from chronic anemia affects regulation of Akt and the MAPKs and if this response is developmentally regulated.
Anemia was created by 7 days of isovolumic hemorrhage beginning at 101 days (early GA) or 129 days (late GA) gestational age (GA) in fetal sheep (term = 145 days), following which protein levels of total and active Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun NH2-terminal kinase (JNK), and p38 were determined in the right and left ventricle (RV and LV). RV protein-to-DNA ratios were also assessed.
At both GAs, ventricular (RV + LV + septum) weight normalized to body weight was significantly increased in anemic fetuses. Anemia had no effect on expression of myocardial total or active Akt, JNK, or p38 at either GA. Levels of total ERK1/2 were also unchanged, although active ERK1/2 was significantly decreased in the late but not early GA anemic fetuses. Total JNK and total and active ERK1/2 and Akt were significantly greater in early versus late GA anemic fetuses. Protein-to-DNA ratios were unchanged in response to anemia at both GAs, but were greater in late GA compared to early GA anemic fetuses.
These results identify important developmental differences in the response of the MAPKs and Akt in the stressed fetal heart. Differences in protein-to-DNA ratios likely reflect the different populations of cardiomyocytes composing the fetal heart at these two GAs and their cell-dependent response to a hemodynamic load.
蛋白激酶B（Akt）和丝裂原活化蛋白激酶（MAPK）介导成年心脏肥大，尽管它们在发育中心脏中的重要性尚不清楚。本研究的目的是确定慢性贫血导致的胎儿心脏容量负荷是否会影响Akt和MAPK的调节，以及这种反应是否受发育调控。
在胎羊（足月=145天）妊娠101天（孕早期）或129天（孕晚期）开始进行7天的等容性出血以造成贫血，之后测定右心室和左心室（RV和LV）中总Akt和活性Akt、细胞外信号调节激酶1/2（ERK1/2）、c-Jun氨基末端激酶（JNK）和p38的蛋白水平。还评估了右心室蛋白与DNA的比率。
在两个孕周，贫血胎儿的心室（RV+LV+室间隔）重量与体重的比值均显著增加。贫血对任一孕周心肌总Akt或活性Akt、JNK或p38的表达均无影响。总ERK1/2水平也未改变，尽管晚期而非早期贫血胎儿的活性ERK1/2显著降低。早期贫血胎儿的总JNK、总ERK1/2、活性ERK1/2和Akt均显著高于晚期贫血胎儿。两个孕周的贫血均未改变蛋白与DNA的比率，但晚期贫血胎儿的该比率高于早期贫血胎儿。
这些结果确定了应激胎儿心脏中MAPK和Akt反应的重要发育差异。蛋白与DNA比率的差异可能反映了这两个孕周组成胎儿心脏的心肌细胞群体不同，以及它们对血流动力学负荷的细胞依赖性反应。
