Impaired insulin-signaling in hypertrophied hearts contributes to ischemic injury.
Despite increased glucose utilization by hypertrophied myocardium, these hearts exhibit a slower rate of glucose uptake (GU). We hypothesized that, in hypertrophied myocardium, a defect of the insulin-responsive glucose transporter is responsible for impaired GU and metabolism during ischemia, contributing to post-ischemic myocardial dysfunction. In a rabbit model of pressure-overload hypertrophy, GU ((31)P NMR spectroscopy) and total/phosphorylated insulin-signaling intermediates were assayed: insulin-receptor, insulin-receptor-substrate-1 (IRS-1), phosphatidylinositol-3-kinase (PI3-k), GLUT-4 translocation and contractile function in an isolated heart ischemia/reperfusion model. Total protein was not different between hypertrophied and control hearts. Phosphorylation of IRS-1 and PI3-k activity was significantly lower in hypertrophy during ischemia. GU was impaired pre-ischemia in hypertrophy, remained lower during early reperfusion, and was associated with impaired recovery of contractile function. In conclusion, a defect in IRS-1 phosphorylation and PI3-k activation in hypertrophied hearts restricts insulin-mediated GLUT-4 translocation and ischemia, a known stimulus of GLUT-4 translocation, does not compensate for this defect.
Friehs
Ingeborg
I
Department of Cardiac Surgery, Children's Hospital Boston and Harvard Medical School, Boston, USA.
Cao-Danh
Hung
H
Nathan
Meena
M
McGowan
Francis X
FX
del Nido
Pedro J
PJ
D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000502:physiology*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009200:Myocardial Contraction; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000503:physiopathology; D011817:Rabbits; D015398:Signal Transduction
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D005947:Glucose