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

Abstract

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. The heart of the anemic fetus must adapt to an increased workload in the face of decreased oxygen carrying capacity of the blood. In fetal sheep, several hemodynamic adaptations occur acutely that serve to maintain optimal tissue perfusion. Arteriolar resistance to vital organs, including the heart, brain, and adrenal glands, declines, allowing preservation of adequate substrate delivery (1). Stroke volume increases, along with cardiac work, to support the compensatory increase in cardiac output (2).Chronically, anemia has a profound affect on myocardial architecture, including biventricular hypertrophy accompanied by myocardial vessel growth, as demonstrated by an increase in minimal capillary diameter and a reduction in intercapillary distance (3,4). These adaptations serve to decrease ventricular wall stress and provide enhanced myocardial substrate and oxygen delivery. Interestingly, even with myocardial vessel growth, coronary flow reserve is maintained, allowing the heart to respond to additional stresses placed on the fetus (5).Metabolic adaptations must accompany the structural changes of the myocardium as cardiac workload increases with acute anemia and is maintained at elevated levels with chronic anemia. An increase in substrate delivery to the myocyte is crucial if normal function is to be maintained. The fetal heart primarily oxidizes glucose and lactate to generate ATP (6), and, in the chronically anemic f...

Myocardial vascular and metabolic adaptations in chronically anemic fetal sheep

“…Furthermore, myocardial glucose and lactate consumption remained unchanged and there was no net lactate production, suggesting aerobic metabolism was preserved. Our group (26) similarly found in a subgroup of anemic fetuses described in the present study that, although serum lactate increased, suggesting systemic hypoxemia and a shift toward anaerobic metabolism, there was no net myocardial lactate production. Thus the role of in vivo tissue hypoxia in regulating myocardial expression of HIF-1 protein and, in turn, VEGF mRNA is not clear.…”

“…The fetal heart primarily oxidizes glucose and lactate to generate ATP (12). Although significant increases in myocardial glucose or lactate uptake have not been identified in the anemic fetus, studies from our laboratory (26) have demonstrated that myocardial glucose transporter GLUT4 expression is increased and expression of GLUT1 is decreased in chronically anemic fetal sheep. Regulatory mechanisms involving important glycolytic and mitochondrial enzymes perhaps orchestrate the rapid adaptive changes that must occur in response to the increased metabolic requirements of the fetal heart during chronic anemia.…”

Increased myocardial methionine‐enkephalin with reduced arterial oxygenation in congenital heart disease

“…Myocardial adaptation to chronic hypoxia in foetal sheep involves augmented ventricular expression of hypoxia‐inducible factor‐1 (HIF‐1), vascular endothelial growth factor (VEGF) and its receptors, glycolytic enzymes such as aldolase, lactate dehydrogenase A and phosphoglycerokinase 26 . These changes facilitate increased coronary angiogenesis and blood flow in concert with augmented myocardial expression of myocardial glucose transporter isoform 4 (GLUT4) 27 . However, Reddy e t al .…”

Transfusion Effects on Cardiomyocyte Growth and Proliferation in Fetal Sheep After Chronic Anemia

“…Peripheral tissues respond to progressive anemia by demanding more blood flow, and cardiac enlargement in the chronically anemic fetus supports a sustained increase in cardiac output (11). While changes in cardiomyocyte morphology, metabolism and cardiac vascularity (6, 12-14) accompany cardiac growth in response to chronic fetal anemia, it is unclear whether any of these changes are reversible upon resolution of anemia. We approached this problem by examining the cardiomyocyte response following transfusion of autologous red blood cells to anemic fetuses.…”