Hypoxia during postnatal development results in systemic inflammation, growth retardation and extensive cardiac compensatory adaptation

Abstract

Increasingly, hypoxia is viewed as an important disease mechanism in both childhood asthma and obesity. In children, hypoxia results in chronic inflammation. We investigated the potential of a neonatal rat hypoxia model (Hx) for the study of inflammation. Hypoxia (12% O2) during postnatal day 2 to 20, resulted in a profound decrement in growth similar to that seen in growth restriction (Gr) due to large liter size (Hx pups 47% smaller than control (NC). Hx animals exhibited a 40% increase in Tumor Necrosis Factor-α and a 2-fold increase in Interleukin-6, while circulating Growth Hormone, Insulin Like Growth Factor-I and Vascular Endothelial Growth Factor were depressed (57, 60, and 33% respectively). Despite this non-anabolic milieu, Hx pups demonstrated a remarkable set of compensatory adaptations not seen in Gr of a similar size. In Hx, the left & right ventricles (LV, RV) were 2.3-fold & 4.8-fold, larger than in NC (mg/g body). Contractile protein content in the RV was 2 fold higher and the expression of slow β-myosin heavy chain was increased 18 fold. Adaptive mechanisms appeared to include a decrease in myostatin (−3 fold, mRNA), miR1(−14%) and IGFBP5 (−42% mRNA) levels. These results indicate that local regulatory mechanisms can respond to functional demands in the face of dramatically decreased growth promoting signals and increased inflammatory components. Support - NIH P01HD048721