Gestational Age Affects Activation of The Mitogen-Activated Protein Kinases and Akt in The Chronically Anemic Fetal Sheep Heart

A K Olson; J L Segar; T D Scholz

doi:10.1203/00006450-200410000-00039

Background: The postnatal heart responds to biomechanical stress by myocyte hypertrophy, whereas the fetal heart may additionally undergo hyperplasia. Before 100 d gestational age (GA), nearly 100% of fetal sheep cardiomyocytes are mitotically active, which decreases to about 20% near term. The mitogen-activated protein kinases (MAPKs) and Akt are hypertrophic signaling pathways in adult hearts. The activities of these pathways are not well characterized in the loaded fetal heart. Objective: To test the hypothesis that activation of myocardial p38, c-jun-n terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK 1/2) and Akt by increased cardiac load resulting from chronic anemia is developmentally regulated in early versus late GA sheep. Methods: Anemia was created in fetal sheep at 98 or 134 d GA (term 145 d) by daily isovolemic hemorrhage (20–30 ml or 60–100 ml, respectively) for 7 d (n = 7 for both ages). Age-matched, non-bled twins served as controls. Right (RV) and left ventricular (LV) MAPK and Akt protein levels were determined by Western blot. Data are given as mean ± SE. Results: In 98 d anemic fetuses, hemoglobin (9.4±0.3 g/dL) and arterial oxygen content (7.8±0.4 to 3.3±0.3 mL 02/dL) decreased significantly from days 1 to 8 of the study, while total heart weight normalized to body weight was significantly increased (6.69±0.3 vs 5.69± 0.3g/kg) compared to controls (p< 0.05). RV and LV total and active protein levels of JNK, ERK 1/2 and Akt were similar between 98 d anemic and control fetuses, as were total levels of p38. Compared to the 134 d anemic fetuses, the 98 d anemic fetuses showed significantly greater RV and LV total and active protein levels of ERK and Akt (p<0.05). Total levels of LV p38 and RV and LV JNK were increased in 98 d versus 134 d anemic fetuses although active levels of RV and LV JNK and total levels of RV JNK were unchanged. Conclusions: In contrast to the late GA fetal heart, activity of MAPK pathways in early GA fetal myocardium is not altered by chronic anemia, indicating MAPKs are not essential for adaptation to an increased load. Volume loading of the fetal sheep heart leads to developmentally regulated cell signaling profiles – possibly related to the high percentage of mitotically capable myocytes in the immature fetal heart.

Gestational Age Affects Activation of The Mitogen-Activated Protein Kinases and Akt in The Chronically Anemic Fetal Sheep Heart

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