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The Mitogen-Activated Protein Kinases and Akt Are Developmentally Regulated in the Chronically Anemic Fetal Sheep Heart

Kristen N. Protheroe

Thomas D. Scholz, MD

Department of Pediatrics, Carver College of Medicine, University of lowa, lowa City, lowa

Jeffrey L. Segar, MD

Department of Pediatrics, Carver College of Medicine, University of lowa, lowa City, lowa; Department of Pediatrics, University of lowa, 200 Hawkins Dr., lowa City, IA 52242; jeffreysegar{at}uiowa.edu

Objective: 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.

Methods: 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-toDNA ratios were also assessed.

Results: 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 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-toDNA ratios were unchanged in response to anemia at both GAs, but were greater in late GA compared to early GA anemic fetuses.

Conclusion: These resullts 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.

Key Words: Hypertrophy • hyperplasia • extracellular signal-regulated kinases • c-Jun NH2-terminal kinase • p38 • Akt

Journal of the Society for Gynecologic Investigation, Vol. 13, No. 3, 157-165 (2006)
DOI: 10.1016/j.jsgi.2006.01.004


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