Cardiac-specific overexpression of GLUT1 prevents the development of heart failure attributable to pressure overload in mice.
BACKGROUND: Increased rates of glucose uptake and glycolysis have been repeatedly observed in cardiac hypertrophy and failure. Although these changes have been considered part of the fetal gene reactivation program, the functional significance of increased glucose utilization in hypertrophied and failing myocardium is poorly understood. METHODS AND RESULTS: We generated transgenic (TG) mice with cardiac-specific overexpression of insulin-independent glucose transporter GLUT1 to recapitulate the increases in basal glucose uptake rate observed in hypertrophied hearts. Isolated perfused TG hearts showed a greater rate of basal glucose uptake and glycolysis than hearts isolated from wild-type littermates, which persisted after pressure overload by ascending aortic constriction (AAC). The in vivo cardiac function in TG mice, assessed by echocardiography, was unaltered. When subjected to AAC, wild-type mice exhibited a progressive decline in left ventricular (LV) fractional shortening accompanied by ventricular dilation and decreased phosphocreatine to ATP ratio and reached a mortality rate of 40% at 8 weeks. In contrast, TG-AAC mice maintained LV function and phosphocreatine to ATP ratio and had <10% mortality. CONCLUSIONS: We found that increasing insulin-independent glucose uptake and glycolysis in adult hearts does not compromise cardiac function. Furthermore, we demonstrate that increasing glucose utilization in hypertrophied hearts protects against contractile dysfunction and LV dilation after chronic pressure overload.
Pubmed ID: 12379584 RIS Download
Adenosine Triphosphate | Animals | Aorta | Biological Transport | Constriction | Echocardiography | Glucose | Glucose Transporter Type 1 | Heart Failure | Humans | Hypertrophy, Left Ventricular | Mice | Mice, Transgenic | Monosaccharide Transport Proteins | Myocardial Contraction | Myocardium | Organ Culture Techniques | Phosphocreatine | Pressure | Survival Analysis | Ventricular Remodeling