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Regulation of Myocardial Glucose Transporters GLUT1 and GLUT4 in Chronically Anemic Fetal Lambs

Little is known about the chronic adaptations that take place in the fetal heart to allow for increased substrate delivery in response to chronic stress. Because glucose is an important fuel for the fetal cardiomyocytes, we hypothesized that myocardial glucose transporters 1 and 4 (GLUT1 and GLUT4, respectively) are up-regulated in the fetal sheep heart that is chronically stressed by anemia. Fetal sheep at 128 d gestation underwent daily isovolumic hemorrhage and determination of myocardial blood flow, oxygen consumption, and substrate utilization. At the end of 3 or 7 d of anemia, myocardial levels of GLUT1 and GLUT4 mRNA and protein were measured and subcellular localization was determined. Despite stable heart rate and blood pressure, anemia caused a nearly 4-fold increase in right and left ventricular (RV and LV) free wall blood flow. No significant change in myocardial glucose uptake was found and serum insulin levels remained stable. Both 3-d RV and LV and 7-d RV mRNA and protein levels of GLUT1 and GLUT4 were unchanged; 7-d LV GLUT1 and GLUT4 mRNA levels were also stable. However, LV GLUT1 protein levels declined significantly, whereas LV GLUT4 protein levels were increased. In the steady state, GLUT4 protein localized to the sarcolemma membrane. These findings suggest that the glucose transporters are post-transcriptionally regulated in myocardium of chronically anemic fetal sheep with changes that mimic normal postnatal development. Unlike the postnatal heart, localization of GLUT4 to the cell membrane suggests the importance of GLUT4 in basal glucose uptake in the stressed fetal heart.